Piperazine thiazole derivatives useful in the treatment of tauopathies such as Alzheimer&#39;s disease

ABSTRACT

The present invention relates to a compound of formula (IA), wherein G 1  is lower alkyl; lower alkyl substituted by one or more halogens; cycloalkyl; tetrahydropyran-4-yl; phenethyl; phenethyl substituted by one or more halogens; phenoxymethyl; phenoxymethyl substituted by one or more halogens; benzyloxyethyl; benzyloxy-ethyl substituted by one or more halogens; or is —NR 2 R 3 ; R 2  is hydrogen or lower alkyl; R 3  is lower alkyl; tetrahydropyran-4-yl; —CH 2 -cycloalkyl; or cycloalkyl optionally substituted by lower alkyl substituted by one or more halogens; or R 2  and R 3  form together with the N-atom to which they are attached a heterocycloalkyl group with 4 or 5 carbon atoms, which is optionally substituted by one or more substituents selected from halogen; or lower alkyl substituted by one or more halogens; X is —CH 2 — or —(CH 2 ) 2 —; Ar is phenyl or pyridinyl; R 4  is halogen; lower alkyl; lower alkyl substituted by one or more halogens; or lower alkoxy; n is 1 or 2; or to a pharmaceutically active salt thereof, to a stereoisomeric form, including an individual diastereoisomer or enantiomer of the compound of formula (IA) as well as to a racemic or non-racemic mixture thereof. The present invention also relates to the use of a compound of formula (IA) for treating certain neurodegenerative disorders characterized by cytotoxic TAU misfolding and/or aggregation.

RELATED APPLICATIONS

The present application is a continuation of U.S. application Ser. No.14/238,905, filed Feb. 14, 2014, which is a 35 U.S.C. §371 filing ofInternational Application No. PCT/EP2012/066136, filed Aug. 17, 2012;which claims priority to European Patent Application No. 11177742.1,filed on Aug. 17, 2011. The entire contents of each are incorporatedherein by reference.

FIELD OF THE INVENTION

The present invention relates to piperazine thiazoles and their use fortreating certain neurodegenerative disorders characterized by cytotoxicTAU misfolding and/or aggregation.

BACKGROUND OF THE INVENTION

TAU is a protein with the ability to bind—and consequently stabilise anddefine—microtubule structure and function in neurons. The binding of TAUto microtubules is regulated by phosphorylation of TAU and several TAUphosphorylation sites and their corresponding kinases have beenidentified which control phosphorylation status of TAU and consequentlymodulate the affinity of TAU-binding to microtubules.

Hyperphosphorylation of TAU cause it to aggregate in an insoluble form.(These aggregations of hyperphosphorylated TAU protein are also referredto as PHF, or “paired helical filaments”). Tauopathies are characterisedby insoluble aggregates or polymers of hyperphosphorylated TAU which areformed by self-polymerisation of TAU monomers.

An important aspect of the TAU aggregation is its associatedcytotoxicity which reduces neuronal integrity and functionality andultimately resulting in disease symptoms. A direct role of TAU indisease onset has been established unequivocally by the elucidation offamilial mutations in TAU which appear to be responsible for a veryearly and sometimes aggressive form of tauopathy. Such mutationscomprise changes in the amino acid sequence of TAU that—directly orindirectly—promote neurotoxic aggregation.

Alzheimer's disease is the best known of these, where TAU protein isdeposited within neurons in the form of neurofibrillary tangles (NFTs).They were first described by the eponymous Alois Alzheimer in one of hispatients suffering from the disorder.

Currently used treatments for tauopathies, including Alzheimer'sdisease, offer only symptomatic benefit without impacting the underlyingneurodegeneration.

WO2007/090617 discloses substituted 1,2,4-thiadiazole derivatives foruse in the treatment of an α-synucleopathy such as Parkinson's disease,diffuse Lewy body disease, traumatic brain injury, amyotrophic lateralsclerosis, Niemann-Pick disease, Hallervorden-Spatz syndrome, Downsyndrome, neuroaxonal dystrophy, multiple system atrophy and Alzheimer'sdisease.

Treatments aimed to suppress cytotoxic TAU misfolding and/or aggregationin order to delay or halt the progression of disease are presently notavailable. Thus there is a need for new treatments that target theunderlying molecular mechanism of noxious TAU misfolding and/oraggregation in order to reduce neuronal cell death and/or degenerationin patients suffering from tauopathies such as Alzheimer's disease.

SUMMARY OF THE INVENTION

A first aspect of the present invention relates to compounds of formulaIA or to a pharmaceutically active salt thereof, to a stereoisomericform, including an individual diastereoisomer or enantiomer of thecompound of formula IA as well as to a racemic or non-racemic mixturethereof;

wherein

-   G¹ is lower alkyl; lower alkyl substituted by one or more halogens;    cycloalkyl; tetrahydropyran-4-yl; phenethyl; phenethyl substituted    by one or more halogens; phenoxymethyl; phenoxymethyl substituted by    one or more halogens; benzyloxy-ethyl; benzyloxy-ethyl substituted    by one or more halogens; or is —NR²R³;-   R² is hydrogen or lower alkyl;-   R³ is lower alkyl; tetrahydropyran-4-yl; —CH₂-cycloalkyl; or    cycloalkyl optionally substituted by lower alkyl substituted by one    or more halogens; or R² and R³ form together with the N-atom to    which they are attached a heterocycloalkyl group with 4 or 5 carbon    atoms, which is optionally substituted by one or more substituents    selected from halogen; or lower alkyl substituted by one or more    halogens;-   X is —CH₂— or —(CH₂)₂—;-   Ar is phenyl or pyridinyl;-   R⁴ is halogen; lower alkyl; lower alkyl substituted by one or more    halogens; or lower alkoxy;-   n is 1 or 2;    with the proviso that said compound is not:-   5-(4-(3-fluorobenzyl)piperazin-1-yl)-3-methyl-1,2,4-thiadiazole and-   3-isopropyl-5-(4-(3-(trifluoromethyl)benzyl)piperazin-1-yl)-1,2,4-thiadiazole.

A second aspect of the invention relates to a process for preparation ofcompounds of formula IA according to a first aspect of the invention,which process comprises coupling a compound of formula

with a compound of formula

to give a compound of formula

wherein the definitions are as described in the first aspect of theinvention, wherein PG is hydrogen or a protecting group, such astert-butyloxycarbonyl (BOC), 9-fluorenylmethyloxycarbonyl (FMOC) and thelike, and hal is a halogen or if desired, converting the compoundsobtained into pharmaceutically acceptable acid addition salts.

A third aspect of the invention relates to a medicament containing oneor more compounds according to the first aspect of the invention andpharmaceutically acceptable excipients.

A fourth aspect of the invention relates to a medicament according tothe third aspect, for use in the treatment of a disease selected fromthe group consisting of are Alzheimer's disease, Pick's disease,corticobasal degeneration, progressive supranuclear palsy,frontotemporal dementia, and parkinsonism (linked to chromosome 17,FTDP-17).

A fifth aspect of the invention relates to the use of a compoundaccording to the first aspect of the invention for the manufacture ofmedicaments for the treatment of Alzheimer's disease, Pick's disease,corticobasal degeneration, progressive supranuclear palsy,frontotemporal dementia and parkinsonism (linked to chromosome 17,FTDP-17).

A sixth aspect of the invention relates to a method for the treatment ofAlzheimer's disease, Pick's disease, corticobasal degeneration,progressive supranuclear palsy, frontotemporal dementia and parkinsonism(linked to chromosome 17, FTDP-17), which method comprisingadministering an effective amount of a compound as defined in the firstaspect of the invention.

DETAILED DESCRIPTION

In an embodiment, the present invention encompasses a compound offormula IA, wherein,

G¹ is lower alkyl; lower alkyl substituted by one or more halogens;cycloalkyl; tetrahydropyran-4-yl; phenethyl; phenethyl substituted byone or more halogens; phenoxymethyl; phenoxymethyl substituted by one ormore halogens; benzyloxy-ethyl; benzyloxy-ethyl substituted by one ormore halogens; or is —NR²R³; preferably, G¹ is C₁₋₇alkyl; C₁₋₇alkylsubstituted by one or more halogens; C₃₋₆cycloalkyl;tetrahydropyran-4-yl; phenethyl; phenethyl substituted by one or morehalogens; phenoxymethyl; phenoxymethyl substituted by one or morehalogens; benzyloxy-ethyl; benzyloxy-ethyl substituted by one or morehalogens; or is —NR²R³; preferably G¹ is lower alkyl; cycloalkyl;tetrahydropyran-4-yl; phenoxymethyl substituted by one or more halogens;benzyloxy-ethyl; benzyloxy-ethyl substituted by one or more halogens; oris —NR²R³; preferably, G¹ is lower alkyl; cycloalkyl; phenoxymethylsubstituted by one or more halogens; benzyloxy-ethyl; benzyloxy-ethylsubstituted by one or more halogens; or is —NR²R³; preferably, G¹ islower alkyl; phenoxymethyl substituted by one or more halogens;benzyloxy-ethyl substituted by halogen; or is —NR²R³; preferably, G¹ isC₁₋₇alkyl; phenoxymethyl substituted by one or more halogens;benzyloxy-ethyl substituted by one or more halogens; or is —NR²R³;R² is hydrogen or lower alkyl; preferably R² is hydrogen or C₁₋₇alkylR³ is lower alkyl; tetrahydropyran-4-yl; —CH₂-cycloalkyl; cycloalkyloptionally substituted by lower alkyl substituted by one or morehalogens; or R² and R³ form together with the N-atom to which they areattached a heterocycloalkyl group with 4 or 5 carbon atoms, which isoptionally substituted by one or more substituents selected fromhalogen; or lower alkyl substituted by one or more halogens; preferably,R³ is C₁₋₇alkyl; tetrahydropyran-4-yl; —CH₂—C₃₋₆cycloalkyl;C₃₋₆cycloalkyl optionally substituted by C₁₋₇alkyl substituted by one ormore halogens; or R² and R³ form together with the N-atom to which theyare attached a heterocycloalkyl group with 4 or 5 carbon atoms, which isoptionally substituted by one or more substituents selected fromhalogen; or C₁₋₇alkyl substituted by one or more halogens; or R² and R³form together with the N-atom to which they are attached aheterocycloalkyl group with 4 or 5 carbon atoms, which is optionallysubstituted by one or more substituents selected from halogen; orC₁₋₇alkyl substituted by one or more halogens; preferably, R³ istetrahydropyran-4-yl; —CH₂-cycloalkyl; cycloalkyl optionally substitutedby lower alkyl substituted by one or more halogens; or R² and R³ formtogether with the N-atom to which they are attached a heterocycloalkylgroup with 4 or 5 carbon atoms, which is optionally substituted by oneor more substituents selected from halogen; or lower alkyl substitutedby one or more halogens; preferably, R³ is cycloalkyl optionallysubstituted by lower alkyl substituted by one or more halogens; or R²and R³ form together with the N-atom to which they are attached aheterocycloalkyl group with 4 or 5 carbon atoms, which is optionallysubstituted by one or more substituents selected from halogen; or loweralkyl substituted by one or more halogens;X is —CH₂— or —(CH₂)₂—; preferably X is —(CH₂)₂;Ar is phenyl or pyridinyl; preferably Ar is phenyl;R⁴ is halogen; lower alkyl; lower alkyl substituted by one or morehalogens; or lower alkoxy; preferably R⁴ is halogen; C₁₋₇alkyl;C₁₋₇alkyl substituted by one or more halogens; or C₁₋₇alkoxy; preferablyR⁴ is halogen; lower alkyl substituted by one or more halogens; or loweralkoxy; preferably R⁴ is halogen; or lower alkoxy;n is 1 or 2; preferably, n is 1.

In an embodiment, the present invention provides compounds of formulaIA, wherein, G¹ is C₁₋₆alkyl; C₁₋₆alkyl substituted by one or morehalogens; C₃₋₆cycloalkyl; tetrahydropyran-4-yl; phenethyl; phenethylsubstituted by one or more halogens; phenoxymethyl; phenoxymethylsubstituted by one or more halogens; benzyloxy-ethyl; benzyloxy-ethylsubstituted by one or more halogens; or is —NR²R³; preferably, G¹ isC₁₋₆alkyl; C₃₋₆cycloalkyl; tetrahydropyran-4-yl; phenoxymethylsubstituted by one or more halogens; benzyloxy-ethyl; benzyloxy-ethylsubstituted by one or more halogens; or is —NR²R³; preferably, G¹ isC₁₋₆alkyl; C₃₋₆cycloalkyl; phenoxymethyl substituted by one or morehalogens; benzyloxy-ethyl; benzyloxy-ethyl substituted by one or morehalogens; or is —NR²R³; preferably, G¹ is C₁₋₆alkyl; phenoxymethylsubstituted by one or more halogens; benzyloxy-ethyl; benzyloxy-ethylsubstituted by one or more halogens; or is —NR²R³;

R² is hydrogen or C₁₋₆alkyl;

R³ is C₁₋₆alkyl; tetrahydropyran-4-yl; —CH₂₋₆cycloalkyl; C₃₋₆cycloalkyloptionally substituted by C₁₋₆alkyl substituted by one or more halogens;or R² and R³ form together with the N-atom to which they are attached aheterocycloalkyl group with 4 or 5 carbon atoms, which is optionallysubstituted by one or more substituents selected from halogen; orC₁₋₆alkyl substituted by one or more halogens; preferably, R³ istetrahydropyran-4-yl; —CH₂₋₆cycloalkyl; C₃₋₆cycloalkyl optionallysubstituted by C₁₋₆alkyl substituted by one or more halogens; or R² andR³ form together with the N-atom to which they are attached aheterocycloalkyl group with 4 or 5 carbon atoms, which is optionallysubstituted by one or more substituents selected from halogen; orC₁₋₆alkyl substituted by one or more halogens; preferably, R³ isC₃₋₆cycloalkyl optionally substituted by C₁₋₆alkyl substituted by one ormore halogens; or R² and R³ form together with the N-atom to which theyare attached a heterocycloalkyl group with 4 or 5 carbon atoms, which isoptionally substituted by one or more substituents selected fromhalogen; or C₁₋₆alkyl substituted by one or more halogens;X is —CH₂— or —(CH₂)₂—; preferably X is —(CH₂)₂;Ar is phenyl or pyridinyl; preferably Ar is phenyl;R⁴ is halogen; C₁₋₆alkyl; C₁₋₆alkyl substituted by one or more halogens;or C₁₋₆alkoxy; preferably R⁴ is halogen; C₁₋₆alkyl substituted by one ormore halogens; or C₁₋₆alkoxy; preferably R⁴ is halogen; or C₁₋₆alkoxy;n is 1 or 2; preferably, n is 1.

In an embodiment, the present invention encompasses a compound offormula IA, wherein, G¹ is selected from: lower alkyl; cycloalkyl;tetrahydropyran-4-yl; phenoxymethyl substituted by one or more halogens;benzyloxy-ethyl; benzyloxy-ethyl substituted by one or more halogens; or—NR²R³;

In another particular embodiment of the present invention, the compoundshave a structure according to formula IA, wherein G¹ is —NR²R³ and R³ iscycloalkyl optionally substituted by lower alkyl substituted by one ormore halogens; or R² and R³ form together with the N-atom to which theyare attached a heterocycloalkyl group with 4 or 5 carbon atoms, which isoptionally substituted by one or more substituents selected fromhalogen; or lower alkyl substituted by one or more halogens.

In an embodiment, the present invention encompasses a compound offormula IA, wherein, G¹ is selected from: lower alkyl; cycloalkyl;tetrahydropyran-4-yl; phenoxymethyl substituted by one or more halogens;benzyloxy-ethyl; benzyloxy-ethyl substituted by one or more halogens; or—NR²R³; and X is —(CH₂)₂; yet more in particular G¹ is lower alkyl orphenoxymethyl substituted by one or more halogens; yet more inparticular G¹ is benzyloxy-ethyl; or phenoxymethyl substituted by one ormore halogens; yet more in particular G¹ is phenoxymethyl substituted byone or more halogens.

In an embodiment, the present invention encompasses a compound offormula IA, wherein, X is —(CH₂)₂.

In an embodiment, the present invention encompasses a compound offormula IA, wherein Ar is phenyl.

In an embodiment, the present invention encompasses a compound offormula IA, wherein, G¹ is selected from: lower alkyl; cycloalkyl;tetrahydropyran-4-yl; phenoxymethyl substituted by one or more halogens;benzyloxy-ethyl; benzyloxy-ethyl substituted by one or more halogens; or—NR²R³; and Ar is phenyl; yet more in particular G¹ is lower alkyl orbenzyloxy-ethyl; phenoxymethyl substituted by one or more halogens; yetmore in particular G¹ is phenoxymethyl substituted by one or morehalogens.

In an embodiment, the present invention encompasses a compound offormula IA, wherein, G¹ is selected from: lower alkyl; cycloalkyl;tetrahydropyran-4-yl; phenoxymethyl substituted by one or more halogens;benzyloxy-ethyl; benzyloxy-ethyl substituted by one or more halogens; or—NR²R³; and Ar is phenyl; yet more in particular G¹ is lower alkyl orphenoxymethyl substituted by one or more halogens; yet more inparticular G¹ is lower alkyl.

In an embodiment, the present invention encompasses a compound offormula IA, wherein, G¹ is selected from: lower alkyl; cycloalkyl;tetrahydropyran-4-yl; phenoxymethyl substituted by one or more halogens;benzyloxy-ethyl; or benzyloxy-ethyl substituted by one or more halogens.

In another particular embodiment of the present invention, the compoundshave a structure according to formula IA, whereby G¹ is —NR²R³.

In another particular embodiment of the present invention, the compoundshave a structure according to formula IA, whereby G¹ is —NR²R³; R² ishydrogen; and R³ is lower alkyl; tetrahydropyran-4-yl; —CH₂-cycloalkyl;or cycloalkyl optionally substituted by lower alkyl substituted by oneor more halogens.

In another particular embodiment of the present invention, the compoundshave a structure according to formula IA, whereby G¹ is —NR²R³; and R²and R³ form together with the N-atom to which they are attached aheterocycloalkyl group with 4 or 5 carbon atoms, which is optionallysubstituted by one or more substituents selected from halogen; or loweralkyl substituted by one or more halogens.

In another particular embodiment of the present invention, the compoundshave a structure according to formula IA, wherein G¹ is benzyloxy-ethyloptionally substituted by one or more halogens and Ar is phenyl.

In another particular embodiment of the present invention, the compoundshave a structure according to formula IA, wherein G¹ is benzyloxy-ethyl;Ar is phenyl and X is —(CH₂)₂.

In another particular embodiment of the present invention, the compoundshave a structure according to formula IA, wherein G¹ is phenoxymethylsubstituted by one or more halogens and Ar is phenyl.

In another particular embodiment of the present invention, the compoundshave a structure according to formula IA, wherein G¹ is phenoxymethylsubstituted by one or more halogens; Ar is phenyl and X is —(CH₂)₂.

In another particular embodiment of the present invention, the compoundshave a structure according to formula IA, wherein G¹ is lower alkyl andAr is phenyl.

In another particular embodiment of the present invention, the compoundshave a structure according to formula IA, wherein G¹ is lower alkyl; Aris phenyl and X is —(CH₂)₂.

In a particular embodiment of the invention, the compounds have astructure of formula IA, whereby G¹ is —NR²R³; and Ar is phenyl.

In a particular embodiment of the invention, the compounds have astructure of formula IA, whereby G¹ is —NR²R³; Ar is phenyl and R² andR³ form together with the N-atom to which they are attached aheterocycloalkyl group with 4 or 5 carbon atoms, which is optionallysubstituted by one or more substituents selected from halogen; or loweralkyl substituted by one or more halogens.

In a particular embodiment of the invention, the compounds have astructure of formula IA, whereby G¹ is —NR²R³; X is —(CH₂)₂— and R² andR³ form together with the N-atom to which they are attached aheterocycloalkyl group with 4 or 5 carbon atoms, which is optionallysubstituted by one or more substituents selected from halogen; or loweralkyl substituted by one or more halogens.

In a particular embodiment of the invention, the compounds have astructure of formula IA, whereby G¹ is —NR²R³; Ar is phenyl; R² and R³form together with the N-atom to which they are attached aheterocycloalkyl group with 4 or 5 carbon atoms, which is optionallysubstituted by one or more substituents selected from halogen; or loweralkyl substituted by one or more halogens; and X is —(CH₂)₂.

For example, the present invention encompasses compounds of formula IAhaving structural formula I,

wherein R¹ has the same meaning as G¹.

In a particular embodiment, the present invention relates to thefollowing compounds, uses, medicaments and processes:

E1. A compound of formula I

wherein

-   R¹ is lower alkyl; cycloalkyl; tetrahydropyran-4-yl or is —NR²R³;-   R² is hydrogen or lower alkyl;-   R³ is lower alkyl; tetrahydropyran-4-yl; —CH₂-cycloalkyl or    cycloalkyl optionally substituted by lower alkyl substituted by one    or more halogens;    -   or R² and R³ form together with the N-atom to which they are        attached a heterocycloalkyl group with 4 or 5 carbon atoms,        which is optionally substituted by one or more substituents        selected from halogen or lower alkyl substituted by one or more        halogens;-   X is —CH₂— or —(CH₂)₂—;-   Ar is phenyl or pyridinyl;-   R⁴ is halogen, lower alkyl or lower alkyl substituted by one or more    halogens;-   n is 1 or 2;    or to a pharmaceutically active salt thereof, to a stereoisomeric    form, including an individual diastereoisomer or enantiomer of the    compound of formula I as well as to a racemic or non-racemic mixture    thereof.

E2. A compound of formula I according to E1, wherein X is —(CH₂)₂—.

E3. A compound of formula I according to E2, which compounds are:

-   1-[3-(4,4-Difluoro-piperidin-1-yl)-[1,2,4]thiadiazol-5-yl]-4-[2-(4-methoxy-phenyl)-ethyl]-piperazine-   1-[2-(4-Chloro-phenyl)-ethyl]-4-[3-(4,4-difluoro-piperidin-1-yl)-[1,2,4]thiadiazol-5-yl]-piperazine-   1-[2-(4-Chloro-phenyl)-ethyl]-4-[3-(3,3-difluoro-pyrrolidin-1-yl)-[1,2,4]thiadiazol-5-yl]-piperazine-   1-[2-(4-Chloro-phenyl)-ethyl]-4-[3-(4-fluoro-piperidin-1-yl)-[1,2,4]thiadiazol-5-yl]-piperazine-   1-[2-(4-Chloro-phenyl)-ethyl]-4-[3-(4-trifluoromethyl-piperidin-1-yl)-[1,2,4]thiadiazol-5-yl]-piperazine-   1-[2-(4-Chloro-phenyl)-ethyl]-4-(3-piperidin-1-yl-[1,2,4]thiadiazol-5-yl)-piperazine-   (5-{4-[2-(4-Chloro-phenyl)-ethyl]-piperazin-1-yl}-[1,2,4]thiadiazol-3-yl)-cyclopropylmethyl-amine-   (5-{4-[2-(4-Chloro-phenyl)-ethyl]-piperazin-1-yl}-[1,2,4]thiadiazol-3-yl)-(tetrahydro-pyran-4-yl)-amine-   (5-{4-[2-(4-Chloro-phenyl)-ethyl]-piperazin-1-yl}-[1,2,4]thiadiazol-3-yl)-cyclohexyl-amine-   1-[2-(3,4-Difluoro-phenyl)-ethyl]-4-[3-(4,4-difluoro-piperidin-1-yl)-[1,2,4]thiadiazol-5-yl]-piperazine-   1-[2-(3,4-Difluoro-phenyl)-ethyl]-4-[3-(3,3-difluoro-pyrrolidin-1-yl)-[1,2,4]thiadiazol-5-yl]-piperazine-   1-[2-(3,4-Difluoro-phenyl)-ethyl]-4-[3-(4-fluoro-piperidin-1-yl)-[1,2,4]thiadiazol-5-yl]-piperazine-   1-[2-(3,4-Difluoro-phenyl)-ethyl]-4-[3-(4-trifluoromethyl-piperidin-1-yl)-[1,2,4]thiadiazol-5-yl]-piperazine-   1-[2-(3,4-Difluoro-phenyl)-ethyl]-4-(3-pyrrolidin-1-yl-[1,2,4]thiadiazol-5-yl)-piperazine-   Cyclopropylmethyl-(5-{4-[2-(3,4-difluoro-phenyl)-ethyl]-piperazin-1-yl}-[1,2,4]thiadiazol-3-yl)-amine-   (5-{4-[2-(3,4-Difluoro-phenyl)-ethyl]-piperazin-1-yl}-[1,2,4]thiadiazol-3-yl)-(tetrahydro-pyran-4-yl)-amine-   Cyclohexyl-(5-{4-[2-(3,4-difluoro-phenyl)-ethyl]-piperazin-1-yl}-[1,2,4]thiadiazol-3-yl)-amine-   1-[2-(3,4-Difluoro-phenyl)-ethyl]-4-(3-piperidin-1-yl-[1,2,4]thiadiazol-5-yl)-piperazine-   (5-{4-[2-(3,4-Difluoro-phenyl)-ethyl]-piperazin-1-yl}-[1,2,4]thiadiazol-3-yl)-(4-trifluoromethyl-cyclohexyl)-amine-   Butyl-(5-{4-[2-(3,4-difluoro-phenyl)-ethyl]-piperazin-1-yl}-[1,2,4]thiadiazol-3-yl)-ethyl-amine-   1-(3-Cyclohexyl-[1,2,4]thiadiazol-5-yl)-4-[2-(4-methoxy-phenyl)-ethyl]-piperazine-   1-(3-Cyclohexyl-[1,2,4]thiadiazol-5-yl)-4-[2-(3-methoxy-phenyl)-ethyl]-piperazine-   1-(3-Butyl-[1,2,4]thiadiazol-5-yl)-4-[2-(4-methoxy-phenyl)-ethyl]-piperazine-   1-(3-Cyclopropyl-[1,2,4]thiadiazol-5-yl)-4-[2-(4-methoxy-phenyl)-ethyl]-piperazine-   1-(3-Butyl-[1,2,4]thiadiazol-5-yl)-4-[2-(3-methoxy-phenyl)-ethyl]-piperazine-   1-(3-Cyclopropyl-[1,2,4]thiadiazol-5-yl)-4-[2-(3-methoxy-phenyl)-ethyl]-piperazine-   1-[2-(4-Fluoro-phenyl)-ethyl]-4-[3-(tetrahydro-pyran-4-yl)-[1,2,4]thiadiazol-5-yl]-piperazine-   1-[2-(4-Methoxy-phenyl)-ethyl]-4-[3-(tetrahydro-pyran-4-yl)-[1,2,4]thiadiazol-5-yl]-piperazine-   1-[2-(2-Methoxy-pyridin-4-yl)-ethyl]-4-[3-(tetrahydro-pyran-4-yl)-[1,2,4]thiadiazol-5-yl]-piperazine    or-   1-[2-(3,4-Difluoro-phenyl)-ethyl]-4-[3-(tetrahydro-pyran-4-yl)-[1,2,4]thiadiazol-5-yl]-piperazine.

E4. A compound of formula I according to any one of E1-E3, wherein R¹ islower alkyl, cycloalkyl or tetrahydropyran-4-yl.

E5. A compound of formula I according to E4, wherein the compounds are:

-   1-(3-Cyclohexyl-[1,2,4]thiadiazol-5-yl)-4-[2-(4-methoxy-phenyl)-ethyl]-piperazine-   1-(3-Cyclohexyl-[1,2,4]thiadiazol-5-yl)-4-[2-(3-methoxy-phenyl)-ethyl]-piperazine-   1-(3-Butyl-[1,2,4]thiadiazol-5-yl)-4-[2-(4-methoxy-phenyl)-ethyl]-piperazine-   1-(3-Cyclopropyl-[1,2,4]thiadiazol-5-yl)-4-[2-(4-methoxy-phenyl)-ethyl]-piperazine-   1-(3-Butyl-[1,2,4]thiadiazol-5-yl)-4-[2-(3-methoxy-phenyl)-ethyl]-piperazine-   1-(3-Cyclopropyl-[1,2,4]thiadiazol-5-yl)-4-[2-(3-methoxy-phenyl)-ethyl]-piperazine-   1-[2-(4-Fluoro-phenyl)-ethyl]-4-[3-(tetrahydro-pyran-4-yl)-[1,2,4]thiadiazol-5-yl]-piperazine-   1-[2-(4-Methoxy-phenyl)-ethyl]-4-[3-(tetrahydro-pyran-4-yl)-[1,2,4]thiadiazol-5-yl]-piperazine-   1-[2-(2-Methoxy-pyridin-4-yl)-ethyl]-4-[3-(tetrahydro-pyran-4-yl)-[1,2,4]thiadiazol-5-yl]-piperazine    or-   1-[2-(3,4-Difluoro-phenyl)-ethyl]-4-[3-(tetrahydro-pyran-4-yl)-[1,2,4]thiadiazol-5-yl]-piperazine.

E6. A compound of formula I according to any one of E1-E3, wherein R¹ is—NR²R³.

E7. A compound of formula I according to E6, wherein R² is hydrogen andR³ is lower alkyl, tetrahydropyran-4-yl, —CH₂-cycloalkyl or cycloalkyloptionally substituted by lower alkyl substituted by one or morehalogens.

E8. A compound of formula I according to E7, wherein the compounds are

-   (5-{4-[2-(4-Chloro-phenyl)-ethyl]-piperazin-1-yl}-[1,2,4]thiadiazol-3-yl)-cyclopropylmethyl-amine-   (5-{4-[2-(4-Chloro-phenyl)-ethyl]-piperazin-1-yl}-[1,2,4]thiadiazol-3-yl)-(tetrahydro-pyran-4-yl)-amine-   (5-{4-[2-(4-Chloro-phenyl)-ethyl]-piperazin-1-yl}-[1,2,4]thiadiazol-3-yl)-cyclohexyl-amine-   Cyclopropylmethyl-(5-{4-[2-(3,4-difluoro-phenyl)-ethyl]-piperazin-1-yl}-[1,2,4]thiadiazol-3-yl)-amine-   (5-{4-[2-(3,4-Difluoro-phenyl)-ethyl]-piperazin-1-yl}-[1,2,4]thiadiazol-3-yl)-(tetrahydro-pyran-4-yl)-amine-   Cyclohexyl-(5-{4-[2-(3,4-difluoro-phenyl)-ethyl]-piperazin-1-yl}-[1,2,4]thiadiazol-3-yl)-amine    or-   (5-{4-[2-(3,4-Difluoro-phenyl)-ethyl]-piperazin-1-yl}-[1,2,4]thiadiazol-3-yl)-(4-trifluoromethyl-cyclohexyl)-amine

E9. A compound of formula I according to E6, wherein R² and R³ formtogether with the N-atom to which they are attached a heterocycloalkylgroup with 4 or 5 carbon atoms, which is optionally substituted by oneor more substituents selected from halogen or lower alkyl substituted byone or more halogens.

E10. A compound of formula I according to E9, which compounds are:

-   1-[3-(4,4-Difluoro-piperidin-1-yl)-[1,2,4]thiadiazol-5-yl]-4-[2-(4-methoxy-phenyl)-ethyl]-piperazine-   1-[2-(4-Chloro-phenyl)-ethyl]-4-[3-(4,4-difluoro-piperidin-1-yl)-[1,2,4]thiadiazol-5-yl]-piperazine-   1-[2-(4-Chloro-phenyl)-ethyl]-4-[3-(3,3-difluoro-pyrrolidin-1-yl)-[1,2,4]thiadiazol-5-yl]-piperazine-   1-[2-(4-Chloro-phenyl)-ethyl]-4-[3-(4-fluoro-piperidin-1-yl)-[1,2,4]thiadiazol-5-yl]-piperazine-   1-[2-(4-Chloro-phenyl)-ethyl]-4-[3-(4-trifluoromethyl-piperidin-1-yl)-[1,2,4]thiadiazol-5-yl]-piperazine-   1-[2-(4-Chloro-phenyl)-ethyl]-4-(3-piperidin-1-yl-[1,2,4]thiadiazol-5-yl)-piperazine-   1-[2-(3,4-Difluoro-phenyl)-ethyl]-4-[3-(4,4-difluoro-piperidin-1-yl)-[1,2,4]thiadiazol-5-yl]-piperazine-   1-[2-(3,4-Difluoro-phenyl)-ethyl]-4-[3-(3,3-difluoro-pyrrolidin-1-yl)-[1,2,4]thiadiazol-5-yl]-piperazine-   1-[2-(3,4-Difluoro-phenyl)-ethyl]-4-[3-(4-fluoro-piperidin-1-yl)-[1,2,4]thiadiazol-5-yl]-piperazine-   1-[2-(3,4-Difluoro-phenyl)-ethyl]-4-[3-(4-trifluoromethyl-piperidin-1-yl)-[1,2,4]thiadiazol-5-yl]-piperazine-   1-[2-(3,4-Difluoro-phenyl)-ethyl]-4-(3-pyrrolidin-1-yl-[1,2,4]thiadiazol-5-yl)-piperazine    or-   1-[2-(3,4-Difluoro-phenyl)-ethyl]-4-(3-piperidin-1-yl-[1,2,4]thiadiazol-5-yl)-piperazine

E11. A process for preparation of compounds of formula I according toE1, which process comprises

coupling a compound of formula

with a compound of formula

to give a compound of formula

wherein the definitions are as described in E1, or if desired,converting the compounds obtained into pharmaceutically acceptable acidaddition salts.

E12. A compound according to any one of E1-E10, when manufacturedaccording to a process of E11.

E13. A compound according to any one of E1-E10 for use astherapeutically active substance.

E14. A medicament containing one or more compounds as described in anyone of E1 to E10 and pharmaceutically acceptable excipients.

E15. A medicament according to E14, wherein the illnesses which may betreated are Alzheimer's disease, Pick's disease, corticobasaldegeneration, progressive supranuclear palsy, frontotemporal dementiaand parkinsonism (linked to chromosome 17, FTDP-17).

E16. The use of a compound as described in any one of E1-E10 for thetreatment of Alzheimer's disease, Pick's disease, corticobasaldegeneration, progressive supranuclear palsy, frontotemporal dementiaand parkinsonism (linked to chromosome 17, FTDP-17).

E17. The use of a compound as described in any one of E1-E10 for themanufacture of medicaments for the treatment of Alzheimer's disease,Pick's disease, corticobasal degeneration, progressive supranuclearpalsy, frontotemporal dementia and parkinsonism (linked to chromosome17, FTDP-17).

E18. A method for the treatment of Alzheimer's disease, Pick's disease,corticobasal degeneration, progressive supranuclear palsy,frontotemporal dementia and parkinsonism (linked to chromosome 17,FTDP-17), which method comprising administering an effective amount of acompound as defined in any one of E1-E10.

E19. The invention as hereinbefore described.

For example, the present invention encompasses a compound or formula Ior IA wherein G¹ has the same meaning as defined for R¹, wherein,

R¹ is lower alkyl; cycloalkyl; tetrahydropyran-4-yl; or is —NR²R³;preferably, R¹ is C₁₋₇alkyl; C₃₋₆cycloalkyl; tetrahydropyran-4-yl; or is—NR²R³; preferably, R¹ is C₁₋₆alkyl; C₃₋₆cycloalkyl;tetrahydropyran-4-yl; or is —NR²R³; preferably, R¹ is lower alkyl;cycloalkyl; or is —NR²R³; preferably, R¹ is lower alkyl; or is —NR²R³;R² is hydrogen or lower alkyl; preferably R² is hydrogen or C₁₋₇alkyl;preferably R² is hydrogen or C₁₋₆alkyl;R³ is lower alkyl; tetrahydropyran-4-yl; —CH₂-cycloalkyl; cycloalkyloptionally substituted by lower alkyl substituted by one or morehalogens; or R² and R³ form together with the N-atom to which they areattached a heterocycloalkyl group with 4 or 5 carbon atoms, which isoptionally substituted by one or more substituents selected fromhalogen; or lower alkyl substituted by one or more halogens; preferablyR³ is C₁₋₇alkyl; tetrahydropyran-4-yl; —CH₂—C₃₋₆cycloalkyl;C₃₋₆cycloalkyl optionally substituted by C₁₋₇alkyl substituted by one ormore halogens; or R² and R³ form together with the N-atom to which theyare attached a heterocycloalkyl group with 4 or 5 carbon atoms, which isoptionally substituted by one or more substituents selected fromhalogen; or C₁₋₇alkyl substituted by one or more halogens; preferably R³is C₁₋₆alkyl; tetrahydropyran-4-yl; —CH₂—C₃₋₆cycloalkyl; C₃₋₆cycloalkyloptionally substituted by C₁₋₆alkyl substituted by one or more halogens;or R² and R³ form together with the N-atom to which they are attached aheterocycloalkyl group with 4 or 5 carbon atoms, which is optionallysubstituted by one or more substituents selected from halogen; orC₁₋₆alkyl substituted by one or more halogens; preferably, R³ istetrahydropyran-4-yl; —CH₂-cycloalkyl; cycloalkyl optionally substitutedby lower alkyl substituted by one or more halogens; or R² and R³ formtogether with the N-atom to which they are attached a heterocycloalkylgroup with 4 or 5 carbon atoms, which is optionally substituted by oneor more substituents selected from halogen; or lower alkyl substitutedby one or more halogens; preferably, R³ is cycloalkyl optionallysubstituted by lower alkyl substituted by one or more halogens; or R²and R³ form together with the N-atom to which they are attached aheterocycloalkyl group with 4 or 5 carbon atoms, which is optionallysubstituted by one or more substituents selected from halogen; or loweralkyl substituted by one or more halogens;X is —CH₂— or —(CH₂)₂—; preferably X is —(CH₂)₂;Ar is phenyl or pyridinyl; preferably Ar is phenyl;R⁴ is halogen; lower alkyl; or lower alkyl substituted by one or morehalogens; or lower alkoxy; preferably R⁴ is halogen; C₁₋₇alkyl; orC₁₋₇alkyl substituted by one or more halogens; or C₁₋₇alkoxy; preferablyR⁴ is halogen; C₁₋₆alkyl; or C₁₋₆alkyl substituted by one or morehalogens; or C₁₋₆alkoxy; preferably R⁴ is halogen; lower alkylsubstituted by one or more halogens; preferably R⁴ is halogen;n is 1 or 2; preferably, n is 1.

In a yet more particular embodiment, the present invention encompassescompounds according to formula I or IA, wherein, R¹ is selected from:lower alkyl; cycloalkyl; tetrahydropyran-4-yl; or —NR²R³;

In another particular embodiment of the present invention, the compoundshave a structure according to formula I or IA, wherein R¹ is —NR²R³ andR³ is cycloalkyl optionally substituted by lower alkyl substituted byone or more halogens; or R² and R³ form together with the N-atom towhich they are attached a heterocycloalkyl group with 4 or 5 carbonatoms, which is optionally substituted by one or more substituentsselected from halogen; or lower alkyl substituted by one or morehalogens.

In an embodiment, the present invention encompasses a compound offormula I or IA, wherein, R¹ is selected from: lower alkyl; cycloalkyl;tetrahydropyran-4-yl; or —NR²R³; and X is —(CH₂)₂; yet more inparticular R¹ is lower alkyl or cycloalkyl; yet more in particular R¹ islower alkyl.

In an embodiment, the present invention encompasses a compound offormula I or IA, wherein, X is —(CH₂)₂.

In an embodiment, the present invention encompasses compounds of formulaI or IA, wherein Ar is phenyl.

In an embodiment, the present invention encompasses compounds of formulaI or IA, wherein, R¹ is selected from: lower alkyl; cycloalkyl;tetrahydropyran-4-yl; or —NR²R³; and Ar is phenyl; yet more inparticular re is lower alkyl or cycloalkyl; yet more in particular R¹ islower alkyl.

In another particular embodiment of the present invention, the compoundshave a structure according to formula I or IA, whereby R¹ is —NR²R³.

In another particular embodiment of the present invention, the compoundshave a structure according to formula I or IA, whereby R¹ is —NR²R³; R²is hydrogen; and R³ is lower alkyl; tetrahydropyran-4-yl;—CH₂-cycloalkyl; or cycloalkyl optionally substituted by lower alkylsubstituted by one or more halogens.

In another particular embodiment of the present invention, the compoundshave a structure according to formula I or IA, whereby R¹ is —NR²R³; andR² and R³ form together with the N-atom to which they are attached aheterocycloalkyl group with 4 or 5 carbon atoms, which is optionallysubstituted by one or more substituents selected from halogen; or loweralkyl substituted by one or more halogens.

In another particular embodiment of the present invention, the compoundshave a structure according to formula I or IA, wherein R¹ is lower alkyland Ar is phenyl.

In another particular embodiment of the present invention, the compoundshave a structure according to formula I or IA, wherein R¹ is loweralkyl; Ar is phenyl and X is —(CH₂)₂.

In a particular embodiment of the invention, the compounds have astructure of formula I or IA, whereby R¹ is —NR²R³; and Ar is phenyl.

In a particular embodiment of the invention, the compounds have astructure of formula I or IA, whereby R¹ is —NR²R³; Ar is phenyl and R²and R³ form together with the N-atom to which they are attached aheterocycloalkyl group with 4 or 5 carbon atoms, which is optionallysubstituted by one or more substituents selected from halogen; or loweralkyl substituted by one or more halogens.

In a particular embodiment of the invention, the compounds have astructure of formula I or IA, whereby R¹ is —NR²R³; X is —(CH₂)₂— and R²and R³ form together with the N-atom to which they are attached aheterocycloalkyl group with 4 or 5 carbon atoms, which is optionallysubstituted by one or more substituents selected from halogen; or loweralkyl substituted by one or more halogens.

In a particular embodiment of the invention, the compounds have astructure of formula I or IA, whereby R¹ is —NR²R³; Ar is phenyl; R² andR³ form together with the N-atom to which they are attached aheterocycloalkyl group with 4 or 5 carbon atoms, which is optionallysubstituted by one or more substituents selected from halogen; or loweralkyl substituted by one or more halogens; and X is —(CH₂)₂.

In a particular embodiment, the present invention relates to thefollowing compounds, uses, medicaments and processes:

The present compounds are useful for treating certain neurodegenerativedisorders characterized by cytotoxic TAU misfolding and/or aggregationin order to delay or halt the progression of such diseases. Suchdiseases are summarized under the term tauopathy. The term “Tauopathy”refers to a disease characterised by dysfunctioning and/or toxicity ofthe TAU protein, characterised by oligomers, aggregates or polymers ofsaid protein. Such diseases include, but are not limited to, Alzheimer'sdisease, Pick's disease, corticobasal degeneration, progressivesupranuclear palsy, frontotemporal dementia and parkinsonism (linked tochromosome 17, FTDP-17).

Tauopathies are characterised by insoluble aggregates or polymers ofhyperphosphorylated TAU which are formed by self-polymerisation of TAUmonomers. The precise molecular mechanisms involved in TAU aggregationare not precisely known, but may involve a partial denaturation ormisfolding of TAU in conformations which have a high propensity toself-organise into higher order structures. The misfolding andaggregation may be triggered by hyperphosphorylation of TAU, although atpresent it cannot be excluded that such aberrant phosphorylation is aconsequence rather than the cause of aggregation. TAU is a protein withthe ability to bind—and consequently stabilise and define—microtubulestructure and function in neurons. The binding of TAU to microtubules isregulated by phosphorylation of TAU and several TAU phosphorylationsites and their corresponding kinases have been identified which controlphosphorylation status of TAU and consequently modulate the affinity ofTAU-binding to microtubules.

An important aspect of the TAU aggregation is its associatedcytotoxicity which reduces neuronal integrity and functionality andultimately resulting in disease symptoms. A direct role of TAU indisease onset has been established unequivocally by the elucidation offamilial mutations in TAU which appear to be responsible for a veryearly and sometimes aggressive form of tauopathy. Such mutationscomprise changes in the amino acid sequence of TAU that—directly orindirectly—promote neurotoxic aggregation.

Alzheimer's disease (AD) is the best known of these, where TAU proteinis deposited within neurons in the form of neurofibrillary tangles(NFTs). They were first described by the eponymous Alois Alzheimer inone of his patients suffering from the disorder. The term “Alzheimer'sdisease” as used herein, refers to a chronic progressive nervous diseasecharacterised by neurodegeneration with as most important (early)symptom being memory loss. As the disease advances, symptoms may includeconfusion, irritability and aggression, mood swings, language breakdown,long-term memory loss, and the general withdrawal of the sufferer astheir senses decline.

Tangles are formed by hyperphosphorylation of a microtubule-associatedprotein known as TAU, causing it to aggregate in an insoluble form.(These aggregations of hyperphosphorylated TAU protein are also referredto as PHF, or “paired helical filaments”). The precise mechanism oftangle formation is not completely understood, and it is stillcontroversial whether tangles are a primary causative factor in thedisease or play a more peripheral role. AD is also classified as anamyloidosis because of the presence of senile plaques.

Other conditions in which neurofibrillary tangles are commonly observedinclude: progressive supranuclear palsy, dementia pugilistica (chronictraumatic encephalopathy), frontotemporal dementia and parkinsonismlinked to chromosome 17, Lytico-Bodig disease (Parkinson-dementiacomplex of Guam), tangle-predominant dementia with NFTs, similar to AD,but without plaques, ganglioglioma and gangliocytoma,meningioangiomatosis, subacute sclerosing panencephalitis, tuberoussclerosis, Hallervorden-Spatz disease, and lipofuscinosis.

The non-Alzheimer's tauopathies are sometimes grouped together as“Pick's complex”. In Pick's disease and corticobasal degeneration tauproteins are deposited in the form of inclusion bodies within swollen or“ballooned” neurons. Argyrophilic grain disease (AGD), another type ofdementia, is marked by the presence of abundant argyrophilic grains andcoiled bodies on microscopic examination of brain tissue.

Similar compounds as described in formula IA and I of the presentinvention have been described in WO2007/090617.

In comparison with the findings in WO2007/090617, it has been found thatthere was a marked decrease of the clearance (Clint) and lipophilicity,in particular in the human in-vitro microsomes assay. It is veryimportant for a drug to have a moderate or low clearance andlipophilicity, as this often leads to a higher oral bioavailability.Reducing the clearance and lipophilicity of a compound/drug could thenpotentially reduce drastically the daily dose required for efficacy andtherefore give also a much better safety profile as well. Therefore alow clearance and lipophilicity is an essential feature for therapeuticapplicability.

The following examples in table I below highlight these finding, wherethe use of compounds of formula I and IA have led to compounds with alower clearance (Clint) and lipophilicity.

Lipophilicity data were measured with the Carrier mediated distributionsystem (CAMDIS) as described in EP1705474A1.

Microsomal Stability Testing—Assay Description

The microsomal stability assay measures the rate of disappearance of atest compound from an incubation containing human or animal livermicrosomes and metabolic cofactors (typically NADPH). The assay isprimarily used for ranking the relative CYP-mediated metabolismpropensities of compounds within a chemical series and as a guide toselecting sufficiently stable compounds for pharmacokinetics andpharmacodynamics experiments. [In addition to CYPs, microsomally locatedenzymes which also make use of NADPH (such as flavone mono-oxygenases)and those which require no cofactors (such as carboxylesterases) areactive.]

Incubations are performed in 96-well deep-well plates with a finalincubation volume of 600 μL. Incubations contain (finally) 1-20 μM testcompound, 0.5 mg/mL liver microsomes (typically human, rat or mouse) andNADPH regenerating system. 50 μL aliquots are removed after 1, 3, 6, 9,15, 25, 35 and 45 minutes and quenched in 150 μL acetonitrile containinginternal standard. Samples are then cooled and centrifuged beforeanalysis by LC-MS/MS.

Log peak area ratio (test compound peak area/internal standard peakarea) is plotted against incubation time and a linear fit made to thedata with emphasis upon the initial rate of compound disappearance. Theslope of the fit is then used to calculate the intrinsic clearance:Cl_(int)(μL/min/mg)=−slope(min⁻¹)*1000/[protein concentration]

TABLE I

  CLint. (Hum/Rat): 17/80 uL/min/mg protein Example 2 CLint. (Hum/Rat):43/48 uL/min/mg protein Compound claimed in WO2007/090617

  lipophilicity: clog P: 3.9 (logD: 2.93) Example 2 lipohilicity clogP:5.9 Compound claimed in WO2007/090617

As it can be seen in the table above, it has been found a markedincrease of metabolic stability in particular in human in vitromicrosomes.

Objects of the present invention are new compounds of formula I and IAand their pharmaceutically acceptable salts, their use for the treatmentof diseases related to the biological function of dysfunction of TAUprotein, which diseases comprise Alzheimer's disease, Pick's disease,corticobasal degeneration, progressive supranuclear palsy,frontotemporal dementia and parkinsonism (linked to chromosome 17,FTDP-17), their manufacture and medicaments based on a compound inaccordance with the invention in the control or prevention of illnesses.

The preferred indication using the compounds of the present invention isAlzheimer's disease.

As used herein, the term “lower alkyl” denotes a saturated straight- orbranched-chain group containing from 1 to 7 carbon atoms, for example,methyl, ethyl, propyl, isopropyl, n-butyl, i-butyl, 2-butyl, t-butyl andthe like. Preferred alkyl groups are groups with 1-6 carbon atoms. Morepreferred alkyl groups are groups with 1-4 carbon atoms.

As used herein, the term “lower alkyl substituted by one or morehalogens” denotes an alkyl group as defined above, wherein at least onehydrogen atom is replaced by halogen, for example CF₃, CHF₂, CH₂F,CH₂CF₃, CH₂CH₂CF₃, CH₂CF₂CF₃ and the like.

The term “halogen” denotes chlorine, iodine, fluorine and bromine.

The term “cycloalkyl” is an alkylene ring, containing from 3 to 6 carbonring atoms. Preferred is cyclopropyl or cyclohexyl.

The term “R² and R³ form together with the N-atom to which they areattached a heterocycloalkyl group with 4 or 5 carbon atoms” denotes aheterocyclyl ring, which contain at least one N-atom in 1-position, forexample piperidin-1-yl or pyrrolidin-1-yl.

As used herein, the term “lower alkoxy” denotes a group wherein thealkyl residue is as defined above and which is attached via an oxygenatom.

The term “pharmaceutically acceptable acid addition salts” embracessalts with inorganic and organic acids, such as hydrochloric acid,nitric acid, sulfuric acid, phosphoric acid, citric acid, formic acid,fumaric acid, maleic acid, acetic acid, succinic acid, tartaric acid,methane-sulfonic acid, p-toluenesulfonic acid and the like.

One embodiment of the invention are compounds of formula IA, wherein Xis —(CH₂)₂—, for example the following compounds

-   1-[3-(4,4-Difluoro-piperidin-1-yl)-[1,2,4]thiadiazol-5-yl]-4-[2-(4-methoxy-phenyl)-ethyl]-piperazine-   1-[2-(4-Chloro-phenyl)-ethyl]-4-[3-(4,4-difluoro-piperidin-1-yl)-[1,2,4]thiadiazol-5-yl]-piperazine-   1-[2-(4-Chloro-phenyl)-ethyl]-4-[3-(3,3-difluoro-pyrrolidin-1-yl)-[1,2,4]thiadiazol-5-yl]-piperazine-   1-[2-(4-Chloro-phenyl)-ethyl]-4-[3-(4-fluoro-piperidin-1-yl)-[1,2,4]thiadiazol-5-yl]-piperazine-   1-[2-(4-Chloro-phenyl)-ethyl]-4-[3-(4-trifluoromethyl-piperidin-1-yl)-[1,2,4]thiadiazol-5-yl]-piperazine-   1-[2-(4-Chloro-phenyl)-ethyl]-4-(3-piperidin-1-yl)-[1,2,4]thiadiazol-5-yl)-piperazine-   (5-{4-[2-(4-Chloro-phenyl)-ethyl]-piperazin-1-yl}-[1,2,4]thiadiazol-3-yl)-cyclopropylmethyl-amine-   (5-{4-[2-(4-Chloro-phenyl)-ethyl]-piperazin-1-yl}-[1,2,4]thiadiazol-3-yl)-(tetrahydro-pyran-4-yl)-amine-   (5-{4-[2-(4-Chloro-phenyl)-ethyl]-piperazin-1-yl}-[1,2,4]thiadiazol-3-yl)-cyclohexyl-amine-   1-[2-(3,4-Difluoro-phenyl)-ethyl]-4-[3-(4,4-difluoro-piperidin-1-yl)-[1,2,4]thiadiazol-5-yl]-piperazine-   1-[2-(3,4-Difluoro-phenyl)-ethyl]-4-[3-(3,3-difluoro-pyrrolidin-1-yl)-[1,2,4]thiadiazol-5-yl]-piperazine-   1-[2-(3,4-Difluoro-phenyl)-ethyl]-4-[3-(4-fluoro-piperidin-1-yl)-[1,2,4]thiadiazol-5-yl]-piperazine-   1-[2-(3,4-Difluoro-phenyl)-ethyl]-4-[3-(4-trifluoromethyl-piperidin-1-yl)-[1,2,4]thiadiazol-5-yl]-piperazine-   1-[2-(3,4-Difluoro-phenyl)-ethyl]-4-(3-pyrrolidin-1-yl-[1,2,4]thiadiazol-5-yl)-piperazine-   Cyclopropylmethyl-(5-{4-[2-(3,4-difluoro-phenyl)-ethyl]-piperazin-1-yl}-[1,2,4]thiadiazol-3-yl)-amine-   (5-{4-[2-(3,4-Difluoro-phenyl)-ethyl]-piperazin-1-yl}-[1,2,4]thiadiazol-3-yl)-(tetrahydro-pyran-4-yl)-amine-   Cyclohexyl-(5-{4-[2-(3,4-difluoro-phenyl)-ethyl]-piperazin-1-yl}-[1,2,4]thiadiazol-3-yl)-amine-   1-[2-(3,4-Difluoro-phenyl)-ethyl]-4-(3-piperidin-1-yl-[1,2,4]thiadiazol-5-yl)-piperazine-   (5-{4-[2-(3,4-Difluoro-phenyl)-ethyl]-piperazin-1-yl}-[1,2,4]thiadiazol-3-yl)-(4-trifluoromethyl-cyclohexyl)-amine-   Butyl-(5-{4-[2-(3,4-difluoro-phenyl)-ethyl]-piperazin-1-yl}-[1,2,4]thiadiazol-3-yl)-ethyl-amine-   1-(3-Cyclohexyl-[1,2,4]thiadiazol-5-yl)-4-[2-(4-methoxy-phenyl)-ethyl]-piperazine-   1-(3-Cyclohexyl-[1,2,4]thiadiazol-5-yl)-4-[2-(3-methoxy-phenyl)-ethyl]-piperazine-   1-(3-Butyl-[1,2,4]thiadiazol-5-yl)-4-[2-(4-methoxy-phenyl)-ethyl]-piperazine-   1-(3-Cyclopropyl-[1,2,4]thiadiazol-5-yl)-4-[2-(4-methoxy-phenyl)-ethyl]-piperazine-   1-(3-Butyl-[1,2,4]thiadiazol-5-yl)-4-[2-(3-methoxy-phenyl)-ethyl]-piperazine-   1-(3-Cyclopropyl-[1,2,4]thiadiazol-5-yl)-4-[2-(3-methoxy-phenyl)-ethyl]-piperazine-   1-[2-(4-Fluoro-phenyl)-ethyl]-4-[3-(tetrahydro-pyran-4-yl)-[1,2,4]thiadiazol-5-yl]-piperazine-   1-[2-(4-Methoxy-phenyl)-ethyl]-4-[3-(tetrahydro-pyran-4-yl)-[1,2,4]thiadiazol-5-yl]-piperazine-   1-[2-(2-Methoxy-pyridin-4-yl)-ethyl]-4-[3-(tetrahydro-pyran-4-yl)-[1,2,4]thiadiazol-5-yl]-piperazine-   1-[2-(3,4-Difluoro-phenyl)-ethyl]-4-[3-(tetrahydro-pyran-4-yl)-[1,2,4]thiadiazol-5-yl]-piperazine-   3-((3-chlorophenoxy)methyl)-5-(4-(3-methoxyphenethyl)piperazin-1-yl)-1,2,4-thiadiazole-   3-(2-(benzyloxy)ethyl)-5-(4-(3-methoxyphenethyl)piperazin-1-yl)-1,2,4-thiadiazole-   3-((4-fluorophenoxy)methyl)-5-(4-(3-methoxyphenethyl)piperazin-1-yl)-1,2,4-thiadiazole-   3-((4-fluorophenoxy)methyl)-5-(4-(4-methoxyphenethyl)piperazin-1-yl)-1,2,4-thiadiazole    or-   5-(4-(4-methoxyphenethyl)piperazin-1-yl)-3-(trifluoromethyl)-1,2,4-thiadiazole.

One further embodiment of the invention are compounds of formula IAwherein X is —(CH₂)₂— and G¹ is selected from: lower alkyl; cycloalkyl;tetrahydropyran-4-yl; phenoxymethyl substituted by halogen orbenzyloxy-ethyl substituted by halogen, for example the compounds

-   1-(3-Cyclohexyl-[1,2,4]thiadiazol-5-yl)-4-[2-(4-methoxy-phenyl)-ethyl]-piperazine-   1-(3-Cyclohexyl-[1,2,4]thiadiazol-5-yl)-4-[2-(3-methoxy-phenyl)-ethyl]-piperazine-   1-(3-Butyl-[1,2,4]thiadiazol-5-yl)-4-[2-(4-methoxy-phenyl)-ethyl]-piperazine-   1-(3-Cyclopropyl-[1,2,4]thiadiazol-5-yl)-4-[2-(4-methoxy-phenyl)-ethyl]-piperazine-   1-(3-Butyl-[1,2,4]thiadiazol-5-yl)-4-[2-(3-methoxy-phenyl)-ethyl]-piperazine-   1-(3-Cyclopropyl-[1,2,4]thiadiazol-5-yl)-4-[2-(3-methoxy-phenyl)-ethyl]-piperazine-   1-[2-(4-Fluoro-phenyl)-ethyl]-4-[3-(tetrahydro-pyran-4-yl)-[1,2,4]thiadiazol-5-yl]-piperazine-   1-[2-(4-Methoxy-phenyl)-ethyl]-4-[3-(tetrahydro-pyran-4-yl)-[1,2,4]thiadiazol-5-yl]-piperazine-   1-[2-(2-Methoxy-pyridin-4-yl)-ethyl]-4-[3-(tetrahydro-pyran-4-yl)-[1,2,4]thiadiazol-5-yl]-piperazine-   1-[2-(3,4-Difluoro-phenyl)-ethyl]-4-[3-(tetrahydro-pyran-4-yl)-[1,2,4]thiadiazol-5-yl]-piperazine-   3-((3-chlorophenoxy)methyl)-5-(4-(3-methoxyphenethyl)piperazin-1-yl)-1,2,4-thiadiazole-   3-(2-(benzyloxy)ethyl)-5-(4-(3-methoxyphenethyl)piperazin-1-yl)-1,2,4-thiadiazole-   3-((4-fluorophenoxy)methyl)-5-(4-(3-methoxyphenethyl)piperazin-1-yl)-1,2,4-thiadiazole    or-   3-((4-fluorophenoxy)methyl)-5-(4-(4-methoxyphenethyl)piperazin-1-yl)-1,2,4-thiadiazole.

One further embodiment of the invention are compounds of formula IAwherein X is —(CH₂)₂— and G¹ is —NR²R³.

One further embodiment of the invention are compounds of formula IAwherein X is —(CH₂)₂— and G¹ is —NR²R³, R² is hydrogen and R³ is loweralkyl, tetrahydropyran-4-yl, —CH₂-cycloalkyl or cycloalkyl optionallysubstituted by lower alkyl substituted by one or more halogens, forexample the compounds

-   (5-{4-[2-(4-Chloro-phenyl)-ethyl]-piperazin-1-yl}-[1,2,4]thiadiazol-3-yl)-cyclopropylmethyl-amine-   (5-{4-[2-(4-Chloro-phenyl)-ethyl]-piperazin-1-yl}-[1,2,4]thiadiazol-3-yl)-(tetrahydro-pyran-4-yl)-amine-   (5-{4-[2-(4-Chloro-phenyl)-ethyl]-piperazin-1-yl}-[1,2,4]thiadiazol-3-yl)-cyclohexyl-amine-   Cyclopropylmethyl-(5-{4-[2-(3,4-difluoro-phenyl)-ethyl]-piperazin-1-yl}-[1,2,4]thiadiazol-3-yl)-amine-   (5-{4-[2-(3,4-Difluoro-phenyl)-ethyl]-piperazin-1-yl}-[1,2,4]thiadiazol-3-yl)-(tetrahydro-pyran-4-yl)-amine-   Cyclohexyl-(5-{4-[2-(3,4-difluoro-phenyl)-ethyl]-piperazin-1-yl}-[1,2,4]thiadiazol-3-yl)-amine    or-   (5-{4-[2-(3,4-Difluoro-phenyl)-ethyl]-piperazin-1-yl}-[1,2,4]thiadiazol-3-yl)-(4-trifluoromethyl-cyclohexyl)-amine

One further embodiment of the invention are compounds of formula IAwherein X is —(CH₂)₂— and G¹ is —NR²R³, and R² and R³ form together withthe N-atom to which they are attached, a heterocycloalkyl group with 4or 5 carbon atoms, which is optionally substituted by one or moresubstituents selected from halogen or lower alkyl substituted by one ormore halogens, for example the compounds

-   1-[3-(4,4-Difluoro-piperidin-1-yl)-[1,2,4]thiadiazol-5-yl]-4-[2-(4-methoxy-phenyl)-ethyl]-piperazine-   1-[2-(4-Chloro-phenyl)-ethyl]-4-[3-(4,4-difluoro-piperidin-1-yl)-[1,2,4]thiadiazol-5-yl]-piperazine-   1-[2-(4-Chloro-phenyl)-ethyl]-4-[3-(3,3-difluoro-pyrrolidin-1-yl)-[1,2,4]thiadiazol-5-yl]-piperazine-   1-[2-(4-Chloro-phenyl)-ethyl]-4-[3-(4-fluoro-piperidin-1-yl)-[1,2,4]thiadiazol-5-yl]-piperazine-   1-[2-(4-Chloro-phenyl)-ethyl]-4-[3-(4-trifluoromethyl-piperidin-1-yl)-[1,2,4]thiadiazol-5-yl]-piperazine-   1-[2-(4-Chloro-phenyl)-ethyl]-4-(3-piperidin-1-yl-[1,2,4]thiadiazol-5-yl)-piperazine-   1-[2-(3,4-Difluoro-phenyl)-ethyl]-4-[3-(4,4-difluoro-piperidin-1-yl)-[1,2,4]thiadiazol-5-yl]-piperazine-   1-[2-(3,4-Difluoro-phenyl)-ethyl]-4-[3-(3,3-difluoro-pyrrolidin-1-yl)-[1,2,4]thiadiazol-5-yl]-piperazine-   1-[2-(3,4-Difluoro-phenyl)-ethyl]-4-[3-(4-fluoro-piperidin-1-yl)-[1,2,4]thiadiazol-5-yl]-piperazine-   1-[2-(3,4-Difluoro-phenyl)-ethyl]-4-[3-(4-trifluoromethyl-piperidin-1-yl)-[1,2,4]thiadiazol-5-yl]-piperazine-   1-[2-(3,4-Difluoro-phenyl)-ethyl]-4-(3-pyrrolidin-1-yl-[1,2,4]thiadiazol-5-yl)-piperazine-   1-[2-(3,4-Difluoro-phenyl)-ethyl]-4-(3-piperidin-1-yl)-[1,2,4]thiadiazol-5-yl)-piperazine

One further embodiment of the invention are compounds of formula IA,wherein X is —CH₂—, for example the compounds1-(2-Methyl-benzyl)-4-[3-(tetrahydro-pyran-4-yl)-[1,2,4]thiadiazol-5-yl]-piperazineor

-   3-(4-chlorophenethyl)-5-(4-(2-methylbenzyl)piperazin-1-yl)-1,2,4-thiadiazole.

One embodiment of the invention are compounds of formula I, wherein X is—(CH₂)₂—, for example the following compounds:1-[3-(4,4-Difluoro-piperidin-1-yl)-[1,2,4]thiadiazol-5-yl]-4-[2-(4-methoxy-phenyl)-ethyl]-piperazine;1-[2-(4-Chloro-phenyl)-ethyl]-4-[3-(4,4-difluoro-piperidin-1-yl)-[1,2,4]thiadiazol-5-yl]-piperazine;1-[2-(4-Chloro-phenyl)-ethyl]-4-[3-(3,3-difluoro-pyrrolidin-1-yl)-[1,2,4]thiadiazol-5-yl]-piperazine;1-[2-(4-Chloro-phenyl)-ethyl]-4-[3-(4-fluoro-piperidin-1-yl)-[1,2,4]thiadiazol-5-yl]-piperazine;1-[2-(4-Chloro-phenyl)-ethyl]-4-[3-(4-trifluoromethyl-piperidin-1-yl)-[1,2,4]thiadiazol-5-yl]-piperazine;1-[2-(4-Chloro-phenyl)-ethyl]-4-(3-piperidin-1-yl-[1,2,4]thiadiazol-5-yl)-piperazine;(5-{4-[2-(4-Chloro-phenyl)-ethyl]-piperazin-1-yl}-[1,2,4]thiadiazol-3-yl)-cyclopropylmethyl-amine;(5-{4-[2-(4-Chloro-phenyl)-ethyl]-piperazin-1-yl}-[1,2,4]thiadiazol-3-yl)-(tetrahydro-pyran-4-yl)-amine;(5-{4-[2-(4-Chloro-phenyl)-ethyl]-piperazin-1-yl}-[1,2,4]thiadiazol-3-yl)-cyclohexyl-amine;1-[2-(3,4-Difluoro-phenyl)-ethyl]-4-[3-(4,4-difluoro-piperidin-1-yl)-[1,2,4]thiadiazol-5-yl]-piperazine;1-[2-(3,4-Difluoro-phenyl)-ethyl]-4-[3-(3,3-difluoro-pyrrolidin-1-yl)-[1,2,4]thiadiazol-5-yl]-piperazine;1-[2-(3,4-Difluoro-phenyl)-ethyl]-4-[3-(4-fluoro-piperidin-1-yl)-[1,2,4]thiadiazol-5-yl]-piperazine;1-[2-(3,4-Difluoro-phenyl)-ethyl]-4-[3-(4-trifluoromethyl-piperidin-1-yl)-[1,2,4]thiadiazol-5-yl]-piperazine;1-[2-(3,4-Difluoro-phenyl)-ethyl]-4-(3-pyrrolidin-1-yl-[1,2,4]thiadiazol-5-yl)-piperazine;Cyclopropylmethyl-(5-{4-[2-(3,4-difluoro-phenyl)-ethyl]-piperazin-1-yl}-[1,2,4]thiadiazol-3-yl)-amine;(5-{4-[2-(3,4-Difluoro-phenyl)-ethyl]-piperazin-1-yl}-[1,2,4]thiadiazol-3-yl)-(tetrahydro-pyran-4-yl)-amine;Cyclohexyl-(5-{4-[2-(3,4-difluoro-phenyl)-ethyl]-piperazin-1-yl}-[1,2,4]thiadiazol-3-yl)-amine;1-[2-(3,4-Difluoro-phenyl)-ethyl]-4-(3-piperidin-1-yl-[1,2,4]thiadiazol-5-yl)-piperazine;(5-{4-[2-(3,4-Difluoro-phenyl)-ethyl]-piperazin-1-yl}-[1,2,4]thiadiazol-3-yl)-(4-trifluoromethyl-cyclohexyl)-amine;Butyl-(5-{4-[2-(3,4-difluoro-phenyl)-ethyl]-piperazin-1-yl}-[1,2,4]thiadiazol-3-yl)-ethyl-amine;1-(3-Cyclohexyl-[1,2,4]thiadiazol-5-yl)-4-[2-(4-methoxy-phenyl)-ethyl]-piperazine;1-(3-Cyclohexyl-[1,2,4]thiadiazol-5-yl)-4-[2-(3-methoxy-phenyl)-ethyl]-piperazine;1-(3-Butyl-[1,2,4]thiadiazol-5-yl)-4-[2-(4-methoxy-phenyl)-ethyl]-piperazine;1-(3-Cyclopropyl-[1,2,4]thiadiazol-5-yl)-4-[2-(4-methoxy-phenyl)-ethyl]-piperazine;1-(3-Butyl-[1,2,4]thiadiazol-5-yl)-4-[2-(3-methoxy-phenyl)-ethyl]-piperazine;1-(3-Cyclopropyl-[1,2,4]thiadiazol-5-yl)-4-[2-(3-methoxy-phenyl)-ethyl]-piperazine;1-[2-(4-Fluoro-phenyl)-ethyl]-4-[3-(tetrahydro-pyran-4-yl)-[1,2,4]thiadiazol-5-yl]-piperazine;1-[2-(4-Methoxy-phenyl)-ethyl]-4-[3-(tetrahydro-pyran-4-yl)-[1,2,4]thiadiazol-5-yl]-piperazine;1-[2-(2-Methoxy-pyridin-4-yl)-ethyl]-4-[3-(tetrahydro-pyran-4-yl)-[1,2,4]thiadiazol-5-yl]-piperazineor1-[2-(3,4-Difluoro-phenyl)-ethyl]-4-[3-(tetrahydro-pyran-4-yl)-[1,2,4]thiadiazol-5-yl]-piperazine.

One further embodiment of the invention are compounds of formula I,wherein R¹ is lower alkyl, cycloalkyl or tetrahydropyran-4-yl, forexample the following compounds:1-(3-Cyclohexyl-[1,2,4]thiadiazol-5-yl)-4-[2-(4-methoxy-phenyl)-ethyl]-piperazine;1-(3-Cyclohexyl-[1,2,4]thiadiazol-5-yl)-4-[2-(3-methoxy-phenyl)-ethyl]-piperazine;1-(3-Butyl-[1,2,4]thiadiazol-5-yl)-4-[2-(4-methoxy-phenyl)-ethyl]-piperazine;1-(3-Cyclopropyl-[1,2,4]thiadiazol-5-yl)-4-[2-(4-methoxy-phenyl)-ethyl]-piperazine;1-(3-Butyl-[1,2,4]thiadiazol-5-yl)-4-[2-(3-methoxy-phenyl)-ethyl]-piperazine;1-(3-Cyclopropyl-[1,2,4]thiadiazol-5-yl)-4-[2-(3-methoxy-phenyl)-ethyl]-piperazine;1-[2-(4-Fluoro-phenyl)-ethyl]-4-[3-(tetrahydro-pyran-4-yl)-[1,2,4]thiadiazol-5-yl]-piperazine;1-[2-(4-Methoxy-phenyl)-ethyl]-4-[3-(tetrahydro-pyran-4-yl)-[1,2,4]thiadiazol-5-yl]-piperazine;1-[2-(2-Methoxy-pyridin-4-yl)-ethyl]-4-[3-(tetrahydro-pyran-4-yl)-[1,2,4]thiadiazol-5-yl]-piperazine;or1-[2-(3,4-Difluoro-phenyl)-ethyl]-4-[3-(tetrahydro-pyran-4-yl)-[1,2,4]thiadiazol-5-yl]-piperazine.

One further embodiment of the invention are compounds of formula I,wherein R² is hydrogen and R³ is lower alkyl, tetrahydropyran-4-yl,—CH₂-cycloalkyl or cycloalkyl optionally substituted by lower alkylsubstituted by one or more halogens, for example the followingcompounds:(5-{4-[2-(4-Chloro-phenyl)-ethyl]-piperazin-1-yl}-[1,2,4]thiadiazol-3-yl)-cyclopropylmethyl-amine;(5-{4-[2-(4-Chloro-phenyl)-ethyl]-piperazin-1-yl}-[1,2,4]thiadiazol-3-yl)-(tetrahydro-pyran-4-yl)-amine;(5-{4-[2-(4-Chloro-phenyl)-ethyl]-piperazin-1-yl}-[1,2,4]thiadiazol-3-yl)-cyclohexyl-amine;Cyclopropylmethyl-(5-{4-[2-(3,4-difluoro-phenyl)-ethyl]-piperazin-1-yl}-[1,2,4]thiadiazol-3-yl)-amine;(5-{4-[2-(3,4-Difluoro-phenyl)-ethyl]-piperazin-1-yl}-[1,2,4]thiadiazol-3-yl)-(tetrahydro-pyran-4-yl)-amine;Cyclohexyl-(5-{4-[2-(3,4-difluoro-phenyl)-ethyl]-piperazin-1-yl}-[1,2,4]thiadiazol-3-yl)-amine;or(5-{4-[2-(3,4-Difluoro-phenyl)-ethyl]-piperazin-1-yl}-[1,2,4]thiadiazol-3-yl)-(4-trifluoromethyl-cyclohexyl)-amine

One further embodiment of the invention are compounds of formula I,wherein R² and R³ form together with the N-atom to which they areattached a heterocycloalkyl group with 4 or 5 carbon atoms, which isoptionally substituted by one or more substituents selected from halogenor lower alkyl substituted by one or more halogens, for examplecompounds:1-[3-(4,4-Difluoro-piperidin-1-yl)-[1,2,4]thiadiazol-5-yl]-4-[2-(4-methoxy-phenyl)-ethyl]-piperazine;1-[2-(4-Chloro-phenyl)-ethyl]-4-[3-(4,4-difluoro-piperidin-1-yl)-[1,2,4]thiadiazol-5-yl]-piperazine;1-[2-(4-Chloro-phenyl)-ethyl]-4-[3-(3,3-difluoro-pyrrolidin-1-yl)-[1,2,4]thiadiazol-5-yl]-piperazine;1-[2-(4-Chloro-phenyl)-ethyl]-4-[3-(4-fluoro-piperidin-1-yl)-[1,2,4]thiadiazol-5-yl]-piperazine;1-[2-(4-Chloro-phenyl)-ethyl]-4-[3-(4-trifluoromethyl-piperidin-1-yl)-[1,2,4]thiadiazol-5-yl]-piperazine;1-[2-(4-Chloro-phenyl)-ethyl]-4-(3-piperidin-1-yl)-[1,2,4]thiadiazol-5-yl)-piperazine;1-[2-(3,4-Difluoro-phenyl)-ethyl]-4-[3-(4,4-difluoro-piperidin-1-yl)-[1,2,4]thiadiazol-5-yl]-piperazine;1-[2-(3,4-Difluoro-phenyl)-ethyl]-4-[3-(3,3-difluoro-pyrrolidin-1-yl)-[1,2,4]thiadiazol-5-yl]-piperazine;1-[2-(3,4-Difluoro-phenyl)-ethyl]-4-[3-(4-fluoro-piperidin-1-yl)-[1,2,4]thiadiazol-5-yl]-piperazine;1-[2-(3,4-Difluoro-phenyl)-ethyl]-4-[3-(4-trifluoromethyl-piperidin-1-yl)-[1,2,4]thiadiazol-5-yl]-piperazine;1-[2-(3,4-Difluoro-phenyl)-ethyl]-4-(3-pyrrolidin-1-yl-[1,2,4]thiadiazol-5-yl)-piperazine;or1-[2-(3,4-Difluoro-phenyl)-ethyl]-4-(3-piperidin-1-yl)-[1,2,4]thiadiazol-5-yl)-piperazine

One further embodiment of the invention are compounds of formula I,wherein R² is lower alkyl, for example the compound:Butyl-(5-{4-[2-(3,4-difluoro-phenyl)-ethyl]-piperazin-1-yl}-[1,2,4]thiadiazol-3-yl)-ethyl-amine.

The present compounds of formula IA or I and their pharmaceuticallyacceptable salts can be prepared by methods known in the art, forexample, by processes described below, which process comprises couplinga compound of formula

with a compound of formula

to give a compound of formula

wherein PG is hydrogen or a protecting group such astert-butyloxycarbonyl (BOC), 9-fluorenylmethyloxycarbonyl (FMOC) and thelike, and hal is halogen such as chloro, bromo, fluoro, or iodo, whereinthe definitions are as described above; or if desired, converting thecompounds obtained into pharmaceutically acceptable acid addition salts.In an embodiment, R¹ has the same meaning as defined for G¹.General Experimental Part

The preparation of compounds of formula IA or I of the present inventionmay be carried out in sequential or convergent synthetic routes.Syntheses of the compounds of the invention are shown in the followingschemes. The skills required for carrying out the reactions andpurifications of the resulting products are known to those skilled inthe art. The substituents and indices used in the following descriptionof the processes have the significance given herein before unlessindicated to the contrary. In more detail, the compounds of formula IAor I can be manufactured by the methods given below, by the methodsgiven in the examples or by analogous methods. Appropriate reactionconditions for the individual reaction steps are known to a personskilled in the art. Also, for reaction conditions described inliterature affecting the described reactions see for example:Comprehensive Organic Transformations: A Guide to Functional GroupPreparations, 2nd Edition, Richard C. Larock. John Wiley & Sons, NewYork, N.Y. 1999). We find it convenient to carry out the reactions inthe presence or absence of a solvent. There is no particular restrictionon the nature of the solvent to be employed, provided that it has noadverse effect on the reaction or the reagents involved and that it candissolve the reagents, at least to some extent. The described reactionscan take place over a wide range of temperatures, and the precisereaction temperature is not critical to the invention. It is convenientto carry out the described reactions in a temperature range between −78°C. to reflux. The time required for the reaction may also vary widely,depending on many factors, notably the reaction temperature and thenature of the reagents. However, a period of from 0.5 h to several dayswill usually suffice to yield the described intermediates and compounds.The reaction sequence is not limited to the one displayed in theschemes, however, depending on the starting materials and theirrespective reactivity the sequence of reaction steps can be freelyaltered. Starting materials are either commercially available or can beprepared by methods analogous to the methods given below, by methodsdescribed in references cited in the description or in the examples, orby methods known in the art.

In an embodiment, R¹ has the same meaning as defined for G¹.

a) Amidines II are either commercially available or can be synthesizedaccording to methods known in the art. These amidine derivatives II areconveniently reacted with perchloromethyl mercaptan with a base (NEt₃,DIPEA and the like) to afford chloro-thiadiazole derivatives III.b) Chloro-thiadiazole derivatives III are conveniently reacted witheither substituted piperazine derivatives to directly access finalthiadiazole derivatives I or alternatively III is reacted with aprotected piperazine (PG=Boc, and the like) to afford thiadiazolederivatives IV.c) Deprotection of IV is done under suitable conditions, in case ofPG=Boc under acidic conditions, to yield the free piperazine derivativeswhich are conveniently reacted with suitable electrophiles, such ashal-X—Ar—(R⁴)_(n) to access final thiadiazole derivatives I.

d) 3-Bromo-5-chloro-1,2,4-thiadiazole and 3,5-dichloro-1,2,4-thiadiazoleV are commercially available and can conveniently be reacted withprotected (PG=Boc and the like) or substituted piperazines to yieldthiadiazole derivatives VI or IX.e) Thiadiazole derivatives VI or IX are conveniently reacted withsuitable amines to yield in case of IX the final derivatives I or incase of VI the protected thiadiazole derivatives VII.f) Deprotection of VII is done under suitable conditions, in case ofPG=Boc under acidic conditions, to yield the free piperazine derivativeswhich are conveniently reacted with suitable electrophiles, such ashal-X—Ar—(R⁴)₁, to access final thiadiazole derivatives I.

EXPERIMENTAL PART Abbreviations

DCM=dichloromethane;

DIPEA=N,N-diisopropylethylamine;

EtOH=ethanol;

Et₃N=triethylamine;

HPLC=high pressure liquid chromatography;

Exemplary compounds of the present invention are listed in table II

TABLE 2 Example Chemical name 11-[3-(4,4-Difluoro-piperidin-1-yl)-[1,2,4]thiadiazol-5-yl]-4-[2-(4-methoxy-phenyl)-ethyl]-piperazine 21-[2-(4-Chloro-phenyl)-ethyl]-4-[3-(4,4-difluoro-piperidin-1-yl)-[1,2,4]thiadiazol-5-yl]-piperazine 31-[2-(4-Chloro-phenyl)-ethyl]-4-[3-(3,3-difluoro-pyrrolidin-1-yl)-[l,2,4]thiadiazol-5-yl]-piperazine 41-[2-(4-Chloro-phenyl)-ethyl]-4-[3-(4-fluoro-piperidin-1-yl)-[1,2,4]thiadiazol-5-yl]-piperazine 51-[2-(4-Chloro-phenyl)-ethyl]-4-[3-(4-trifluoromethyl-piperidin-1-yl)-[1,2,4]thiadiazol-5- yl]-piperazine 61-[2-(4-Chloro-phenyl)-ethyl]-4-(3-piperidin-1-yl-[1,2,4]thiadiazol-5-yl)-piperazine 7(5-{4-[2-(4-Chloro-phenyl)-ethyl]-piperazin-1-yl}-[1,2,4]thiadiazol-3-yl)-cyclopropylmethyl-amine 8(5-{4-[2-(4-Chloro-phenyl)-ethyl]-piperazin-1-yl}-[1,2,4]thiadiazol-3-yl)-(tetrahydro-pyran-4-yl)-amine 9(5-{4-[2-(4-Chloro-phenyl)-ethyl]-piperazin-1-yl}-[1,2,4]thiadiazol-3-yl)-cyclohexyl-amine 101-[2-(3,4-Difluoro-phenyl)-ethyl]-4-[3-(4,4-difluoro-piperidin-1-yl)-[1,2,4]thiadiazol-5-yl]-piperazine 111-[2-(3,4-Difluoro-phenyl)-ethyl]-4-[3-(3,3-difluoro-pyrrolidin-1-yl)-[1,2,4]thiadiazol-5-yl]-piperazine 121-[2-(3,4-Difluoro-phenyl)-ethyl]-4-[3-(4-fluoro-piperidin-1-yl)-[1,2,4]thiadiazol-5-yl]-piperazine 131-[2-(3,4-Difluoro-phenyl)-ethyl]-4-[3-(4-trifluoromethyl-piperidin-1-yl)-[1,2,4]thiadiazol-5- yl]-piperazine 141-[2-(3,4-Difluoro-phenyl)-ethyl]-4-(3-pyrrolidin-1-yl-[1,2,4]thiadiazol-5-yl)-piperazine 15Cyclopropylmethyl-(5-{4-[2-(3,4-difluoro-phenyl)-ethyl]-piperazin-1-yl}-[1,2,4]thiadiazol-3-yl)-amine 16(5-{4-[2-(3,4-Difluoro-phenyl)-ethyl]-piperazin-1-yl}-[1,2,4]thiadiazol-3-yl)-(tetrahydro-pyran-4-yl)- amine 17Cyclohexyl-(5-{4-[2-(3,4-difluoro-phenyl)-ethyl]-piperazin-1-yl}-[1,2,4]thiadiazol-3-yl)-amine 181-[2-(3,4-Difluoro-phenyl)-ethyl]-4-(3-piperidin-1-yl-[1,2,4]thiadiazol-5-yl)-piperazine 19(5-{4-[2-(3,4-Difluoro-phenyl)-ethyl]-piperazin-1-yl}-[1,2,4]thiadiazol-3-yl)-(4-trifluoromethyl- cyclohexyl)-amine 20Butyl-(5-{4-[2-(3,4-difluoro-phenyl)-ethyl]-piperazin-1-yl}-[1,2,4]thiadiazol-3-yl)-ethyl-amine 211-(3-Cyclohexyl-[1,2,4]thiadiazol-5-yl)-4-[2-(4-methoxy-phenyl)-ethyl]-piperazine 221-(3-Cyclohexyl-[1,2,4]thiadiazol-5-yl)-4-[2-(3-methoxy-phenyl)-ethyl]-piperazine 231-(3-Butyl-[1,2,4]thiadiazol-5-yl)-4-[2-(4-methoxy-phenyl)-ethyl]-piperazine 241-(3-Cyclopropyl-[1,2,4]thiadiazol-5-yl)-4-[2-(4-methoxy-phenyl)-ethyl]-piperazine 251-(3-Butyl-[1,2,4]thiadiazol-5-yl)-4-[2-(3-methoxy-phenyl)-ethyl]-piperazine 261-(3-Cyclopropyl-[1,2,4]thiadiazol-5-yl)-4-[2-(3-methoxy-phenyl)-ethyl]-piperazine 271-[2-(4-Fluoro-phenyl)-ethyl]-4-[3-(tetrahydro-pyran-4-yl)-[1,2,4]thiadiazol-5-yl]-piperazine 281-[2-(4-Methoxy-phenyl)-ethyl]-4-[3-(tetrahydro-pyran-4-yl)-[1,2,4]thiadiazol-5-yl]-piperazine 291-[2-(2-Methoxy-pyridin-4-yl)-ethyl]-4-[3-(tetrahydro-pyran-4-yl)-[1,2,4]thiadiazol-5-yl]- piperazine 301-(2-Methyl-benzyl)-4-[3-(tetrahydro-pyran-4-yl)-[1,2,4]thiadiazol-5-yl]-piperazine 311-[2-(3,4-Difluoro-phenyl)-ethyl]-4-[3-(tetrahydro-pyran-4-yl)-[1,2,4]thiadiazol-5-yl]-piperazine 323-(4-chlorophenethyl)-5-(4-(2-methylbenzyl)piperazin-1-yl)-1,2,4-thiadiazole 333-((3-chlorophenoxy)methyl)-5-(4-(3-methoxyphenethyl)piperazin-1-yl)-1,2,4-thiadiazole 343-(2-(benzyloxy)ethyl)-5-(4-(3-methoxyphenethyl)piperazin-1-yl)-1,2,4-thiadiazole 353-((4-fluorophenoxy)methyl)-5-(4-(3-methoxyphenethyl)piperazin-1-yl)-1,2,4-thiadiazole 363-((4-fluorophenoxy)methyl)-5-(4-(4-methoxyphenethyl)piperazin-1-yl)-1,2,4-thiadiazole 375-(4-(4-methoxyphenethyl)piperazin-1-yl)-3-(trifluoromethyl)-1,2,4-thiadiazole

Example 11-[3-(4,4-Difluoro-piperidin-1-yl)-[1,2,4]thiadiazol-5-yl]-4-[2-(4-methoxy-phenyl)-ethyl]-piperazine

a)1-(3-Bromo-[1,2,4]thiadiazol-5-yl)-4-[2-(4-methoxy-phenyl)-ethyl]-piperazine

A mixture of 3-bromo-5-chloro-1,2,4-thiadiazole (300 mg, 1.5 mmol),1-(4-methoxyphenethyl)piperazine dihydrochloride (485 mg, 1.65 mmol) andDIPEA (641 mg, 867 μl, 4.96 mmol) in EtOH (10 mL) was stirred over nightat ambient temperature. The mixture was concentrated in vacuo and theresidue was purified by silica column chromatography eluting with agradient formed from heptane and ethyl acetate to yield afterevaporation of the product containing fractions 489 mg (85%) of thetitle compound as off-white solid. MS (m/e): 383.2 (MH⁺).

b)1-[3-(4,4-Difluoro-piperidin-1-yl)-[1,2,4]thiadiazol-5-yl]-4-[2-(4-methoxy-phenyl)-ethyl]-piperazine

A mixture of3-bromo-5-(4-(4-methoxyphenethyl)piperazin-1-yl)-1,2,4-thiadiazole (55mg, 143 μmol), 4,4-difluoropiperidine hydrochloride (67.8 mg, 430 μmol)and DIPEA (185 mg, 251 μl, 1.43 mmol) in N-Methyl-2-pyrrolidinone (1 mL)was heated with microwave at 200° C. for 2.5 h. The amber reactionsolution was purified by preparative HPLC on reversed phase eluting witha gradient formed from acetonitrile, water and NEt₃ to yield afterevaporation of the product containing fractions 41.8 mg (69%) of thetitle compound as off-white solid. MS (m/e): 424.2 (MH⁺).

Example 21-[2-(4-Chloro-phenyl)-ethyl]-4-[3-(4,4-difluoro-piperidin-1-yl)-[1,2,4]thiadiazol-5-yl]-piperazine

a)1-(3-Bromo-[1,2,4]thiadiazol-5-yl)-4-[2-(4-chloro-phenyl)-ethyl]-piperazine

In analogy to the procedure described for the synthesis of1-(3-bromo-[1,2,4]thiadiazol-5-yl)-4-[2-(4-methoxy-phenyl)-ethyl]-piperazine(example 1, step a) the title compound was prepared from3-bromo-5-chloro-1,2,4-thiadiazole and 1-(4-chlorophenethyl)piperazinedihydrochloride as white solid. MS (m/e): 389.1 (MH⁺).

b)1-[2-(4-Chloro-phenyl)-ethyl]-4-[3-(4,4-difluoro-piperidin-1-yl)-[1,2,4]thiadiazol-5-yl]-piperazine

In analogy to the procedure described for the synthesis of1-[3-(4,4-difluoro-piperidin-1-yl)-[1,2,4]thiadiazol-5-yl]-4-[2-(4-methoxy-phenyl)-ethyl]-piperazine(example 1, step b) the title compound was prepared from1-(3-bromo-[1,2,4]thiadiazol-5-yl)-4-[2-(4-chloro-phenyl)-ethyl]-piperazineand 4,4-difluoropiperidine hydrochloride. MS (m/e): 428.3 (MH⁺).

Example 31-[2-(4-Chloro-phenyl)-ethyl]-4-[3-(3,3-difluoro-pyrrolidin-1-yl)-[1,2,4]thiadiazol-5-yl]-piperazine

In analogy to the procedure described for the synthesis of1-[3-(4,4-difluoro-piperidin-1-yl)-[1,2,4]thiadiazol-5-yl]-4-[2-(4-methoxy-phenyl)-ethyl]-piperazine(example 1, step b) the title compound was prepared from1-(3-bromo-[1,2,4]thiadiazol-5-yl)-4-[2-(4-chloro-phenyl)-ethyl]-piperazineand 3,3-difluoropyrrolidine hydrochloride. MS (m/e): 414.3 (MH⁺).

Example 41-[2-(4-Chloro-phenyl)-ethyl]-4-[3-(4-fluoro-piperidin-1-yl)-[1,2,4]thiadiazol-5-yl]-piperazine

In analogy to the procedure described for the synthesis of1-[3-(4,4-difluoro-piperidin-1-yl)-[1,2,4]thiadiazol-5-yl]-4-[2-(4-methoxy-phenyl)-ethyl]-piperazine(example 1, step b) the title compound was prepared from1-(3-bromo-[1,2,4]thiadiazol-5-yl)-4-[2-(4-chloro-phenyl)-ethyl]-piperazineand 4-fluoropiperidine hydrochloride. MS (m/e): 410.2 (MH⁺).

Example 51-[2-(4-Chloro-phenyl)-ethyl]-4-[3-(4-trifluoromethyl-piperidin-1-yl)-[1,2,4]thiadiazol-5-yl]-piperazine

In analogy to the procedure described for the synthesis of1-[3-(4,4-difluoro-piperidin-1-yl)-[1,2,4]thiadiazol-5-yl]-4-[2-(4-methoxy-phenyl)-ethyl]-piperazine(example 1, step b) the title compound was prepared from1-(3-bromo-[1,2,4]thiadiazol-5-yl)-4-[2-(4-chloro-phenyl)-ethyl]-piperazineand 4-(trifluoromethyl)piperidine hydrochloride. MS (m/e): 460.2 (MH⁺).

Example 61-[2-(4-Chloro-phenyl)-ethyl]-4-(3-piperidin-1-yl-[1,2,4]thiadiazol-5-yl)-piperazine

In analogy to the procedure described for the synthesis of1-[3-(4,4-difluoro-piperidin-1-yl)-[1,2,4]thiadiazol-5-yl]-4-[2-(4-methoxy-phenyl)-ethyl]-piperazine(example 1, step b) the title compound was prepared from1-(3-bromo-[1,2,4]thiadiazol-5-yl)-4-[2-(4-chloro-phenyl)-ethyl]-piperazineand piperidine. MS (m/c): 392.2 (MH⁺).

Example 7(5-{4-[2-(4-Chloro-phenyl)-ethyl]-piperazin-1-yl}-[1,2,4]thiadiazol-3-yl)-cyclopropylmethyl-amine

In analogy to the procedure described for the synthesis of1-[3-(4,4-difluoro-piperidin-1-yl)-[1,2,4]thiadiazol-5-yl]-4-[2-(4-methoxy-phenyl)-ethyl]-piperazine(example 1, step b) the title compound was prepared from1-(3-bromo-[1,2,4]thiadiazol-5-yl)-4-[2-(4-chloro-phenyl)-ethyl]-piperazineand cyclopropylmethanamine. MS (m/e): 378.3 (MH^(|)).

Example 8(5-{4-[2-(4-Chloro-phenyl)-ethyl]-piperazin-1-yl}-[1,2,4]thiadiazol-3-yl)-(tetrahydro-pyran-4-yl)-amine

In analogy to the procedure described for the synthesis of1-[3-(4,4-difluoro-piperidin-1-yl)-[1,2,4]thiadiazol-5-yl]-4-[2-(4-methoxy-phenyl)-ethyl]-piperazine(example 1, step b) the title compound was prepared from1-(3-bromo-[1,2,4]thiadiazol-5-yl)-4-[2-(4-chloro-phenyl)-ethyl]-piperazineand tetrahydro-2H-pyran-4-amine. MS (m/e): 408.3 (MH⁺).

Example 9

(5-{4-[2-(4-Chloro-phenyl)-ethyl]-piperazin-1-yl}-[1,2,4]thiadiazol-3-yl)-cyclohexyl-amine

In analogy to the procedure described for the synthesis of1-[3-(4,4-difluoro-piperidin-1-yl)-[1,2,4]thiadiazol-5-yl]-4-[2-(4-methoxy-phenyl)-ethyl]-piperazine(example 1, step b) the title compound was prepared from1-(3-bromo-[1,2,4]thiadiazol-5-yl)-4-[2-(4-chloro-phenyl)-ethyl]-piperazineand cyclohexanamine. MS (m/e): 406.4 (MH⁺).

Example 101-[2-(3,4-Difluoro-phenyl)-ethyl]-4-[3-(4,4-difluoro-piperidin-1-yl)-[1,2,4]thiadiazol-5-yl]-piperazine

a)1-(3-Bromo-[1,2,4]thiadiazol-5-yl)-4-[2-(3,4-difluoro-phenyl)-ethyl]-piperazine

In analogy to the procedure described for the synthesis of1-(3-Bromo-[1,2,4]thiadiazol-5-yl)-4-[2-(4-methoxy-phenyl)-ethyl]-piperazine(example 1, step a) the title compound was prepared from3-bromo-5-chloro-1,2,4-thiadiazole and1-(3,4-difluorophenethyl)piperazine dihydrochloride, as colourlessviscous oil. MS (m/e): 391.2 (MH⁺).

b)1-[2-(3,4-Difluoro-phenyl)-ethyl]-4-[3-(4,4-difluoro-piperidin-1-yl)-[1,2,4]thiadiazol-5-yl]-piperazine

In analogy to the procedure described for the synthesis of1-[3-(4,4-difluoro-piperidin-1-yl)-[1,2,4]thiadiazol-5-yl]-4-[2-(4-methoxy-phenyl)-ethyl]-piperazine(example 1, step b) the title compound was prepared from1-(3-bromo-[1,2,4]thiadiazol-5-yl)-4-[2-(3,4-difluoro-phenyl)-ethyl]-piperazineand 4,4-difluoropiperidine hydrochloride. MS (m/e): 430.3 (MH⁺).

Example 111-[2-(3,4-Difluoro-phenyl)-ethyl]-4-[3-(3,3-difluoro-pyrrolidin-1-yl)-[1,2,4]thiadiazol-5-yl]-piperazine

In analogy to the procedure described for the synthesis of1-[3-(4,4-difluoro-piperidin-1-yl)-[1,2,4]thiadiazol-5-yl]-4-[2-(4-methoxy-phenyl)-ethyl]-piperazine(example 1, step b) the title compound was prepared from1-(3-bromo-[1,2,4]thiadiazol-5-yl)-4-[2-(3,4-difluoro-phenyl)-ethyl]-piperazineand 3,3-difluoropyrrolidine hydrochloride. MS (m/e): 416.3 (MH⁺).

Example 121-[2-(3,4-Difluoro-phenyl)-ethyl]-4-[3-(4-fluoro-piperidin-1-yl)-[1,2,4]thiadiazol-5-yl]-piperazine

In analogy to the procedure described for the synthesis of1-[3-(4,4-difluoro-piperidin-1-yl)-[1,2,4]thiadiazol-5-yl]-4-[2-(4-methoxy-phenyl)-ethyl]-piperazine(example 1, step b) the title compound was prepared from1-(3-bromo-[1,2,4]thiadiazol-5-yl)-4-[2-(3,4-difluoro-phenyl)-ethyl]-piperazineand 4-fluoropiperidine hydrochloride. MS (m/e): 412.3 (MH⁺).

Example 131-[2-(3,4-Difluoro-phenyl)-ethyl]-4-[3-(4-trifluoromethyl-piperidin-1-yl)-[1,2,4]thiadiazol-5-yl]-piperazine

In analogy to the procedure described for the synthesis of1-[3-(4,4-difluoro-piperidin-1-yl)-[1,2,4]thiadiazol-5-yl]-4-[2-(4-methoxy-phenyl)-ethyl]-piperazine(example 1, step b) the title compound was prepared from1-(3-bromo-[1,2,4]thiadiazol-5-yl)-4-[2-(3,4-difluoro-phenyl)-ethyl]-piperazineand 4-(trifluoromethyl)piperidine hydrochloride. MS (m/e): 462.3 (MH⁺).

Example 141-[2-(3,4-Difluoro-phenyl)-ethyl]-4-(3-pyrrolidin-1-yl-[1,2,4]thiadiazol-5-yl)-piperazine

In analogy to the procedure described for the synthesis of1-[3-(4,4-difluoro-piperidin-1-yl)-[1,2,4]thiadiazol-5-yl]-4-[2-(4-methoxy-phenyl)-ethyl]-piperazine(example 1, step b) the title compound was prepared from1-(3-bromo-[1,2,4]thiadiazol-5-yl)-4-[2-(3,4-difluoro-phenyl)-ethyl]-piperazineand pyrrolidine. MS (m/e): 380.3 (MH⁺).

Example 15Cyclopropylmethyl-(5-{4-[2-(3,4-difluoro-phenyl)-ethyl]-piperazin-1-yl}-[1,2,4]thiadiazol-3-yl)-amine

In analogy to the procedure described for the synthesis of1-[3-(4,4-difluoro-piperidin-1-yl)-[1,2,4]thiadiazol-5-yl]-4-[2-(4-methoxy-phenyl)-ethyl]-piperazine(example 1, step b) the title compound was prepared from1-(3-bromo-[1,2,4]thiadiazol-5-yl)-4-[2-(3,4-difluoro-phenyl)-ethyl]-piperazineand cyclopropylmethanamine. MS (m/e): 380.3 (MH⁺).

Example 16(5-{4-[2-(3,4-Difluoro-phenyl)-ethyl]-piperazin-1-yl}-[1,2,4]thiadiazol-3-yl)-(tetrahydro-pyran-4-yl)-amine

In analogy to the procedure described for the synthesis of1-[3-(4,4-difluoro-piperidin-1-yl)-[1,2,4]thiadiazol-5-yl]-4-[2-(4-methoxy-phenyl)-ethyl]-piperazine(example 1, step b) the title compound was prepared from1-(3-bromo-[1,2,4]thiadiazol-5-yl)-4-[2-(3,4-difluoro-phenyl)-ethyl]-piperazineand tetrahydro-2H-pyran-4-amine. MS (m/e): 410.3 (MH⁺).

Example 17Cyclohexyl-(5-{4-[2-(3,4-difluoro-phenyl)-ethyl]-piperazin-1-yl}-[1,2,4]thiadiazol-3-yl)-amine

In analogy to the procedure described for the synthesis of1-[3-(4,4-difluoro-piperidin-1-yl)-[1,2,4]thiadiazol-5-yl]-4-[2-(4-methoxy-phenyl)-ethyl]-piperazine(example 1, step b) the title compound was prepared from1-(3-bromo-[1,2,4]thiadiazol-5-yl)-4-[2-(3,4-difluoro-phenyl)-ethyl]-piperazineand cyclohexanamine. MS (m/c): 408.4 (MH⁺).

Example 181-[2-(3,4-Difluoro-phenyl)-ethyl]-4-(3-piperidin-1-yl-[1,2,4]thiadiazol-5-yl)-piperazine

In analogy to the procedure described for the synthesis of1-[3-(4,4-difluoro-piperidin-1-yl)-[1,2,4]thiadiazol-5-yl]-4-[2-(4-methoxy-phenyl)-ethyl]-piperazine(example 1, step b) the title compound was prepared from1-(3-bromo-[1,2,4]thiadiazol-5-yl)-4-[2-(3,4-difluoro-phenyl)-ethyl]-piperazineand piperidine. MS (m/e): 394.2 (MH⁺).

Example 19(5-{4-[2-(3,4-Difluoro-phenyl)-ethyl]-piperazin-1-yl}[1,2,4]thiadiazol-3-yl)-(4-trifluoromethyl-cyclohexyl)-amine

In analogy to the procedure described for the synthesis of1-[3-(4,4-difluoro-piperidin-1-yl)-[1,2,4]thiadiazol-5-yl]-4-[2-(4-methoxy-phenyl)-ethyl]-piperazine(example 1, step b) the title compound was prepared from1-(3-bromo-[1,2,4]thiadiazol-5-yl)-4-[2-(3,4-difluoro-phenyl)-ethyl]-piperazineand 4-(trifluoromethyl)cyclohexanamine. MS (m/e): 476.2 (MH⁺).

Example 20Butyl-(5-{4-[2-(3,4-difluoro-phenyl)-ethyl]-piperazin-1-yl}-[1,2,4]thiadiazol-3-yl)-ethyl-amine

In analogy to the procedure described for the synthesis of1-[3-(4,4-difluoro-piperidin-1-yl)-[1,2,4]thiadiazol-5-yl]-4-[2-(4-methoxy-phenyl)-ethyl]-piperazine(example 1, step b) the title compound was prepared from1-(3-bromo-[1,2,4]thiadiazol-5-yl)-4-[2-(3,4-difluoro-phenyl)-ethyl]-piperazineand N-ethylbutan-1-amine. MS (m/e): 410.3 (MH⁺).

Example 211-(3-Cyclohexyl-[1,2,4]thiadiazol-5-yl)-4-[2-(4-methoxy-phenyl)-ethyl]-piperazine

a) 5-Chloro-3-cyclohexyl-[1,2,4]thiadiazole

Cyclohexanecarboximidamide (100 mg, 792 μmol) and DIPEA (512 mg, 3.96mmol) in 10 mL DCM at 0-5° C. were treated with perchloromethylmercaptan (147 mg, 792 μmol) in 5 mL DCM and stirred for 1 hr at 0-5° C.The mixture was concentrated in vacuo to give a brown solid which wasused with out further purification in the subsequent step.

b)1-(3-Cyclohexyl-[1,2,4]thiadiazol-5-yl)-4-[2-(4-methoxy-phenyl)-ethyl]-piperazine

A mixture of 5-chloro-3-cyclohexyl-1,2,4-thiadiazole (32.0 mg, 158μmol), 1-(4-methoxyphenethyl)piperazine dihydrochloride (51.0 mg, 174μmol) and DIPEA in EtOH was heated for 30 min at an oil bath temperatureof 90° C. The mixture was subjected to purification by preparative HPLCon reversed phase eluting with a gradient formed from acetonitrile,water and NEt₃ to yield after evaporation of the product containingfractions 13.7 mg (22%) of the title compound as light brown solid. MS(m/e): 387.3 (MH⁺).

Example 221-(3-Cyclohexyl-[1,2,4]thiadiazol-5-yl)-4-[2-(3-methoxy-phenyl)-ethyl]-piperazine

In analogy to the procedure described for the synthesis of1-(3-cyclohexyl-[1,2,4]thiadiazol-5-yl)-4-[2-(4-methoxy-phenyl)-ethyl]-piperazine(example 21, step b) the title compound was prepared from5-chloro-3-cyclohexyl-[1,2,4]thiadiazole and1-(3-methoxyphenethyl)piperazine dihydrochloride as light brown solid.MS (m/e): 387.3 (MH⁺).

Example 231-(3-Butyl-[1,2,4]thiadiazol-5-yl)-4-[2-(4-methoxy-phenyl)-ethyl]-piperazine

In analogy to the procedure described for the synthesis of1-(3-cyclohexyl-[1,2,4]thiadiazol-5-yl)-4-[2-(4-methoxy-phenyl)-ethyl]-piperazine(example 21, step b) the title compound was prepared from3-butyl-5-chloro-[1,2,4]thiadiazole and 1-(4-methoxyphenethyl)piperazinedihydrochloride. MS (m/e): 361.3 (MH⁺).

Example 241-(3-Cyclopropyl-[1,2,4]thiadiazol-5-yl)-4-[2-(4-methoxy-phenyl)-ethyl]-piperazine

In analogy to the procedure described for the synthesis of1-(3-cyclohexyl-[1,2,4]thiadiazol-5-yl)-4-[2-(4-methoxy-phenyl)-ethyl]-piperazine(example 21, step b) the title compound was prepared from5-chloro-3-cyclopropyl-[1,2,4]thiadiazole and1-(4-methoxyphenethyl)piperazine dihydrochloride. MS (m/e): 345.2 (MH⁺).

Example 251-(3-Butyl-[1,2,4]thiadiazol-5-yl)-4-[2-(3-methoxy-phenyl)-ethyl]-piperazine

In analogy to the procedure described for the synthesis of1-(3-cyclohexyl-[1,2,4]thiadiazol-5-yl)-4-[2-(4-methoxy-phenyl)-ethyl]-piperazine(example 21, step b) the title compound was prepared from3-butyl-5-chloro-[1,2,4]thiadiazole and 1-(3-methoxyphenethyl)piperazinedihydrochloride. MS (m/e): 361.3 (MH⁺).

Example 261-(3-Cyclopropyl-[1,2,4]thiadiazol-5-yl)-4-[2-(3-methoxy-phenyl)-ethyl]-piperazine

In analogy to the procedure described for the synthesis of1-(3-cyclohexyl-[1,2,4]thiadiazol-5-yl)-4-[2-(4-methoxy-phenyl)-ethyl]-piperazine(example 21, step b) the title compound was prepared from5-chloro-3-cyclopropyl-[1,2,4]thiadiazole and1-(3-methoxyphenethyl)piperazine dihydrochloride. MS (m/e): 345.2 (MH⁺).

Example 271-[2-(4-Fluoro-phenyl)-ethyl]-4-[3-(tetrahydro-pyran-4-yl)-[1,2,4]thiadiazol-5-yl]-piperazine

In analogy to the procedure described for the synthesis of1-(3-cyclohexyl-[1,2,4]thiadiazol-5-yl)-4-[2-(4-methoxy-phenyl)-ethyl]-piperazine(example 21, step b) the title compound was prepared from5-chloro-3-(tetrahydro-pyran-4-yl)-[1,2,4]thiadiazole and1-(4-fluorophenethyl)piperazine dihydrochloride. MS (m/e): 377.3 (MH⁺).

Example 281-[2-(4-Methoxy-phenyl)-ethyl]-4-[3-(tetrahydro-pyran-4-yl)[1,2,4]thiadiazol-5-yl]-piperazine

In analogy to the procedure described for the synthesis of1-(3-cyclohexyl-[1,2,4]thiadiazol-5-yl)-4-[2-(4-methoxy-phenyl)-ethyl]-piperazine(example 21, step b) the title compound was prepared from5-chloro-3-(tetrahydro-pyran-4-yl)-[1,2,4]thiadiazole and1-(4-methoxyphenethyl)piperazine dihydrochloride. MS (m/e): 389.3 (MH⁺).

Example 291-[2-(2-Methoxy-pyridin-4-yl)-ethyl]-4-[3-(tetrahydro-pyran-4-yl)-[1,2,4]thiadiazol-5-yl]-piperazine

In analogy to the procedure described for the synthesis of1-(3-cyclohexyl)-[1,2,4]thiadiazol-5-yl)-4-[2-(4-methoxy-phenyl)-ethyl]-piperazine(example 21, step b) the title compound was prepared from5-chloro-3-(tetrahydro-pyran-4-yl)-[1,2,4]thiadiazole and1-(2-(2-methoxypyridin-4-yl)ethyl)piperazine trihydrochloride. MS (m/e):390.3 (MH⁺).

Example 301-(2-Methyl-benzyl)-4-[3-(tetrahydro-pyran-4-yl)-[1,2,4]thiadiazol-5-yl]-piperazine

a) 1-[3-(Tetrahydro-pyran-4-yl)-[1,2,4]thiadiazol-5-yl]-piperazine

A mixture of 5-chloro-3-(tetrahydro-2H-pyran-4-yl)-1,2,4-thiadiazole(2.1 g, 10.3 mmol) and piperazine (8.84 g, 103 mmol) in EtOH (50 mL) wasstirred at room temperature and concentrated in vacuo. The residue waspurified by silica column chromatography eluting with a gradient formedfrom DCM, methanol and NH₃ to yield, after evaporation of the productcontaining fractions 2.48 g (95%) of the title compound as light brownsolid. MS (m/e): 255.1 (MH⁺).

b)1-(2-Methyl-benzyl)-4-[3-(tetrahydro-pyran-4-yl)-[1,2,4]thiadiazol-5-yl]-piperazine

A mixture of5-(piperazin-1-yl)-3-(tetrahydro-2H-pyran-4-yl)-1,2,4-thiadiazole (19.1mg, 75.0 μmol), 1-(chloromethyl)-2-methylbenzene (31.6 mg, 225 μmol) andDIPEA (96.9 mg, 131 μL, 750 μmol) in N-methyl-2-pyrrolidinone (1 mL) washeated under microwave irradiation for 10 min at 180° C. The resultingreaction solution was purified by preparative HPLC on reversed phaseeluting with a gradient formed from acetonitrile, water and NEt₃ toyield, after evaporation of the product containing fractions 13 mg (48%)of the title compound. MS (m/e): 359.2 (MH⁺).

Example 311-[2-(3,4-Difluoro-phenyl)-ethyl]-4-[3-(tetrahydro-pyran-4-yl)-[1,2,4]thiadiazol-5-yl]-piperazine

In analogy to the procedure described for the synthesis of1-(2-methyl-benzyl)-4-[3-(tetrahydro-pyran-4-yl)-[1,2,4]thiadiazol-5-yl]-piperazine(example 30, step b) the title compound was prepared from1-[3-(tetrahydro-pyran-4-yl)-[1,2,4]thiadiazol-5-yl]-piperazine and4-(2-bromoethyl)-1,2-difluorobenzene. MS (m/e): 395.2 (MO.

Example 375-(4-(4-methoxyphenethyl)piperazin-1-yl)-3-(trifluoromethyl)-1,2,4-thiadiazole

In analogy to the procedure described for the synthesis of1-(2-methyl-benzyl)-4-[3-(tetrahydro-pyran-4-yl)-[1,2,4]thiadiazol-5-yl]-piperazine(example 30, step b) the title compound is prepared from5-(piperazin-1-yl)-3-(trifluoromethyl)-1,2,4-thiadiazole and1-(2-bromoethyl)-4-methoxybenzene.

Construction of a TAU Gene Over-Expressing Cell Line

A TAU expression plasmid was constructed by sub-cloning the cDNAencoding for human TAU-P301L protein, wherein proline at position 301 issubstituted by a leucine residue, into mammalian expression vectorpcDNA3.1 resulting in the plasmid pcDNA3.1-TAUP301L. Plasmids pcDNA3.1and pcDNA3.1-TAU P301L were transfected into human neuroblastoma cells(BE-M17; ATCC No. CRL2267™) using lipofectamine reagent andsubsequently, independent clonal cell lines with the plasmids stablyintegrated into the genome were selected by antibiotic resistanceselection (Geneticin (G418)), resulting in cell lines M17.pcDNA3 andM17_3TAUP301L. Expression of the TAUP301L gene in the M17_3TAUP301Lcells was confirmed by Western blot analysis.

Use of TAU Expressing Cells as a Model of Neuronal Degeneration

The expression of TAU P301L in M17_3TAU(P301L) cells was found to conferincreased toxicity relative to control cells expressing no TAU after 7days of cell differentiation using retinoic acid (RA). Differentiationof the cells with RA leads to phosphorylation and subsequent aggregationof TAU, inducing a tauopathy in these cells. Cytotoxicity of cells wasmeasured by quantification of lactate dehydrogenase (LDH) levels. Indead cells LDH is leaked out of the cells into the medium due to a lossof plasma-membrane integrity.

Briefly, 3 days preceeding the experiment pre-cultures of M17.pcDNA3 andM17_3TAU(P301L) cells were prepared, starting from a stock culture, at adensity of 50.000-100.000 cells/cm2 in detection medium (Optimem ReducedSerum without phenol red (Gibco, Cat. 31985-047) supplemented with 1%fetal calf serum (FCS), 1 mM sodium pyruvate, 1× non-essential aminoacids (NEAR), 500 μg/ml G418 and 0.5× antibiotic/antimycotic (ABAM)). Atthe day of the experiment these precultures were diluted to ˜0, 1.106cells/ml in detection medium without FCS and 60 μL of this suspension isdispensed per well into a 96-well microtiter plate. After 3 hours ofincubation at 37° C./5% CO2 an equal volume of detection mediumcontaining 2.5 μM RA was added and subsequently incubated for 7 days at37° C./5% CO₂. After 7 days, LDH activity was determined using thePromega Cytotox 96 Non-Radioactive cytotoxicity assay (Cat. G1780),according the manufacturer's instructions. Cytotoxicity is measured asthe ratio of LDH increase in the supernatant divided by the LDH increasein the total cell suspension (sum of the LDH measured in cells andsupernatant). Figure 1 shows toxicity after 7 days of differentiationwith retinoic acid in M17_3TAU(P301L) cells compared to M17.pcDNA3cells. Toxicity is clearly higher in the M17_3TAU(P301L) cellsdemonstrating that it is specifically provoked by the presence of themutant TAU P301 protein.

Use of the Neuroblastoma Tauopathy Model to Screen Compounds

The M17_3TAU(P301L) cell line makes it possible to assess the ability ofnovel compounds to inhibit TAU-induced cytotoxicity. Active inhibitorsof Tauopathy in these cells were found to inhibit cytotoxicity or LDHincrease in the medium of M17_3TAU(P301L) cells treated as described inExample above. Compounds were tested for their ability to hamperTAU-induced toxicity at different concentrations, ranging from lownon-effective concentrations to high potent concentrations. Afterwards,the dose-dependent inhibition curve was used to calculate their EC₅₀(Table III).

Although the pharmacological properties of the compounds disclosed inthis invention vary with structural change, active compounds mostparticularly possess EC₅₀ in a cell-based assay in a range from about0.0005 to 1.0 μM.

The tested compounds show a EC₅₀ value (μM) as shown in table III.

TABLE III Example EC₅₀ (μM) 1 0.0006 2 0.0536 3 0.0088 4 0.0846 5 0.0476 0.0641 7 0.0172 8 0.0522 9 0.0094 10 0.0121 11 0.0114 12 0.0333 130.0153 14 0.1757 15 0.0384 16 0.0345 17 0.0038 18 0.0464 19 0.3403 200.7088 21 0.0022 22 0.003 23 0.0005 24 0.0445 25 0.0022 26 0.4102 270.3088 28 0.0333 29 0.2027 30 0.4135 31 0.3085

The compounds of formula IA or I and the pharmaceutically acceptablesalts of the compounds of formula IA or I can be used as medicaments,e.g. in the form of pharmaceutical preparations. The pharmaceuticalpreparations can be administered orally, e.g. in the form of tablets,coated tablets, dragées, hard and soft gelatine capsules, solutions,emulsions or suspensions. The administration can, however, also beeffected rectally, e.g. in the form of suppositories, or parenterally,e.g. in the form of injection solutions.

The compounds of formula IA or I can be processed with pharmaceuticallyinert, inorganic or organic carriers for the production ofpharmaceutical preparations. Lactose, corn starch or derivativesthereof, talc, stearic acids or its salts and the like can be used, forexample, as such carriers for tablets, coated tablets, dragées and hardgelatine capsules. Suitable carriers for soft gelatine capsules are, forexample, vegetable oils, waxes, fats, semi-solid and liquid polyols andthe like. Depending on the nature of the active substance no carriersare however usually required in the case of soft gelatine capsules.Suitable carriers for the production of solutions and syrups are, forexample, water, polyols, glycerol, vegetable oil and the like. Suitablecarriers for suppositories are, for example, natural or hardened oils,waxes, fats, semi-liquid or liquid polyols and the like.

The pharmaceutical preparations can, moreover, contain preservatives,solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners,colorants, flavorants, salts for varying the osmotic pressure, buffers,masking agents or antioxidants. They can also contain still othertherapeutically valuable substances.

Medicaments containing a compound of formula IA or I or apharmaceutically acceptable salt thereof and a therapeutically inertcarrier are also an object of the present invention, as is a process fortheir production, which comprises bringing one or more compounds offormula IA or I and/or pharmaceutically acceptable acid addition saltsand, if desired, one or more other therapeutically valuable substancesinto a galenical administration form together with one or moretherapeutically inert carriers.

The most preferred indications in accordance with the present inventionare those, which include disorders of the central nervous system, forexample the treatment or prevention of Alzheimer's disease, Pick'sdisease, corticobasal degeneration, progressive supranuclear palsy,frontotemporal dementia and parkinsonism (linked to chromosome 17,FTDP-17).

The dosage can vary within wide limits and will, of course, have to beadjusted to the individual requirements in each particular case. In thecase of oral administration the dosage for adults can vary from about0.01 mg to about 1000 mg per day of a compound of general formula I orof the corresponding amount of a pharmaceutically acceptable saltthereof. The daily dosage may be administered as single dose or individed doses and, in addition, the upper limit can also be exceededwhen this is found to be indicated.

Tablet Formulation (Wet Granulation) mg/tablet Item Ingredients 5 mg 25mg 100 mg 500 mg 1. Compound of formula I 5 25 100 500 2. LactoseAnhydrous DTG 125 105 30 150 3. Sta-Rx 1500 6 6 6 30 4. MicrocrystallineCellulose 30 30 30 150 5. Magnesium Stearate 1 1 1 1 Total 167 167 167831Manufacturing Procedure1. Mix items 1, 2, 3 and 4 and granulate with purified water.2. Dry the granules at 50° C.3. Pass the granules through suitable milling equipment.4. Add item 5 and mix for three minutes; compress on a suitable press.

Capsule Formulation mg/capsule Item Ingredients 5 mg 25 mg 100 mg 500mg 1. Compound of formula I 5 25 100 500 2. Hydrous Lactose 159 123 148— 3. Corn Starch 25 35 40 70 4. Talc 10 15 10 25 5. Magnesium Stearate 12 2 5 Total 200 200 300 600Manufacturing Procedure1. Mix items 1, 2 and 3 in a suitable mixer for 30 minutes.2. Add items 4 and 5 and mix for 3 minutes.3. Fill into a suitable capsule.

The invention claimed is:
 1. A method for treating a patient sufferingfrom Alzheimer's disease, which method comprises administering aneffective amount of a compound of formula IA or a pharmaceuticallyactive salt thereof, a stereoisomeric form, including an individualdiastereoisomer or enantiomer of the compound of formula IA as well as aracemic or non-racemic mixture thereof; to the patient, thereby treatingthe disease;

wherein G¹ is lower alkyl; lower alkyl substituted by one or morehalogens; cycloalkyl; tetrahydropyran-4-yl; phenethyl; phenethylsubstituted by one or more halogens; phenoxymethyl; phenoxymethylsubstituted by one or more halogens; benzyloxy-ethyl; benzyloxy-ethylsubstituted by one or more halogens; or is —NR²R³; R² is hydrogen orlower alkyl; R³ is lower alkyl, tetrahydropyran-4-yl, —CH₂-cycloalkyl orcycloalkyl optionally substituted by lower alkyl substituted by one ormore halogens; or R² and R³ form together with the N-atom to which theyare attached a heterocycloalkyl group with 4 or 5 carbon atoms, which isoptionally substituted by one or more substituents selected from halogenor lower alkyl substituted by one or more halogens; X is —CH₂— or—(CH₂)₂—; Ar is phenyl or pyridinyl; R⁴ is halogen; lower alkyl; loweralkyl substituted by one or more halogens; or lower alkoxy; n is 1 or 2;with the proviso that said compound is not:5-(4-(3-fluorobenzyl)piperazin-1-yl)-3-methyl-1,2,4-thiadiazole or3-isopropyl-5-(4-(3-(trifluoromethyl)benzyl)piperazin-1-yl)-1,2,4-thiadiazole.2. The method according to claim 1, wherein X is —(CH₂)₂—.
 3. The methodaccording to claim 1, wherein G¹ is lower alkyl; cycloalkyl;tetrahydropyran-4-yl; phenoxymethyl substituted by one or more halogens;benzyloxy-ethyl; or benzyloxy-ethyl substituted by one or more halogens.4. The method according to claim 1, wherein G¹ is —NR²R³.
 5. The methodaccording to claim 4, wherein R² is hydrogen and R³ is lower alkyl,tetrahydropyran-4-yl, —CH₂-cycloalkyl, or cycloalkyl optionallysubstituted by lower alkyl substituted by one or more halogens.
 6. Themethod according to claim 4, wherein R² and R³ form together with theN-atom to which they are attached a heterocycloalkyl group with 4 or 5carbon atoms, which is optionally substituted by one or moresubstituents selected from halogen or lower alkyl substituted by one ormore halogens.
 7. The method according to claim 1, wherein G¹ isselected from: lower alkyl; cycloalkyl; tetrahydropyran-4-yl;phenoxymethyl substituted by one or more halogens; benzyloxy-ethyl;benzyloxy-ethyl substituted by one or more halogens; or —NR²R³; and X is—(CH₂)₂.
 8. The method according to claim 1, wherein G¹ is lower alkylor phenoxymethyl substituted by one or more halogens.
 9. The methodaccording to claim 1, wherein said compound is selected from the groupconsisting of:1-[3-(4,4-Difluoro-piperidin-1-yl)-[1,2,4]thiadiazol-5-yl]-4-[2-(4-methoxy-phenyl)-ethyl]-piperazine;1-[2-(4-Chloro-phenyl)-ethyl]-4-[3-(4,4-difluoro-piperidin-1-yl)-[1,2,4]thiadiazol-5-yl]-piperazine;1-[2-(4-Chloro-phenyl)-ethyl]-4-[3-(3,3-difluoro-pyrrolidin-1-yl)-[1,2,4]thiadiazol-5-yl]-piperazine;1-[2-(4-Chloro-phenyl)-ethyl]-4-[3-(4-fluoro-piperidin-1-yl)-[1,2,4]thiadiazol-5-yl]-piperazine;1-[2-(4-Chloro-phenyl)-ethyl]-4-[3-(4-trifluoromethyl-piperidin-1-yl)-[1,2,4]thiadiazol-5-yl]-piperazine;1-[2-(4-Chloro-phenyl)-ethyl]-4-(3-piperidin-1-yl-[1,2,4]thiadiazol-5-yl)-piperazine;(5-{4-[2-(4-Chloro-phenyl)-ethyl]-piperazin-1-yl}-[1,2,4]thiadiazol-3-yl)-cyclopropylmethyl-amine;(5-{4-[2-(4-Chloro-phenyl)-ethyl]-piperazin-1-yl}-[1,2,4]thiadiazol-3-yl)-(tetrahydro-pyran-4-yl)-amine;(5-{4-[2-(4-Chloro-phenyl)-ethyl]-piperazin-1-yl}-[1,2,4]thiadiazol-3-yl)-cyclohexyl-amine;1-[2-(3,4-Difluoro-phenyl)-ethyl]-4-[3-(4,4-difluoro-piperidin-1-yl)-[1,2,4]thiadiazol-5-yl]-piperazine;1-[2-(3,4-Difluoro-phenyl)-ethyl]-4-[3-(3,3-difluoro-pyrrolidin-1-yl)-[1,2,4]thiadiazol-5-yl]-piperazine;1-[2-(3,4-Difluoro-phenyl)-ethyl]-4-[3-(4-fluoro-piperidin-1-yl)-[1,2,4]thiadiazol-5-yl]-piperazine;1-[2-(3,4-Difluoro-phenyl)-ethyl]-4-[3-(4-trifluoromethyl-piperidin-1-yl)-[1,2,4]thiadiazol-5-yl]-piperazine;1-[2-(3,4-Difluoro-phenyl)-ethyl]-4-(3-pyrrolidin-1-yl-[1,2,4]thiadiazol-5-yl)-piperazine;Cyclopropylmethyl-(5-{4-[2-(3,4-difluoro-phenyl)-ethyl]-piperazin-1-yl}-[1,2,4]thiadiazol-3-yl)-amine;(5-{4-[2-(3,4-Difluoro-phenyl)-ethyl]-piperazin-1-yl}-[1,2,4]thiadiazol-3-yl)-(tetrahydro-pyran-4-yl)-amine;Cyclohexyl-(5-{4-[2-(3,4-difluoro-phenyl)-ethyl]-piperazin-1-yl}-[1,2,4]thiadiazol-3-yl)-amine;1-[2-(3,4-Difluoro-phenyl)-ethyl]-4-(3-piperidin-1-yl-[1,2,4]thiadiazol-5-yl)-piperazine;(5-{4-[2-(3,4-Difluoro-phenyl)-ethyl]-piperazin-1-yl}-[1,2,4]thiadiazol-3-yl)-(4-trifluoromethyl-cyclohexyl)-amine;Butyl-(5-{4-[2-(3,4-difluoro-phenyl)-ethyl]-piperazin-1-yl}-[1,2,4]thiadiazol-3-yl)-ethyl-amine;1-(3-Cyclohexyl-[1,2,4]thiadiazol-5-yl)-4-[2-(4-methoxy-phenyl)-ethyl]-piperazine;1-(3-Cyclohexyl-[1,2,4]thiadiazol-5-yl)-4-[2-(3-methoxy-phenyl)-ethyl]-piperazine;1-(3-Butyl-[1,2,4]thiadiazol-5-yl)-4-[2-(4-methoxy-phenyl)-ethyl]-piperazine;1-(3-Cyclopropyl-[1,2,4]thiadiazol-5-yl)-4-[2-(4-methoxy-phenyl)-ethyl]-piperazine;1-(3-Butyl-[1,2,4]thiadiazol-5-yl)-4-[2-(3-methoxy-phenyl)-ethyl]-piperazine;1-(3-Cyclopropyl-[1,2,4]thiadiazol-5-yl)-4-[2-(3-methoxy-phenyl)-ethyl]-piperazine;1-[2-(4-Fluoro-phenyl)-ethyl]-4-[3-(tetrahydro-pyran-4-yl)-[1,2,4]thiadiazol-5-yl]-piperazine;1-[2-(4-Methoxy-phenyl)-ethyl]-4-[3-(tetrahydro-pyran-4-yl)-[1,2,4]thiadiazol-5-yl]-piperazine;1-[2-(2-Methoxy-pyridin-4-yl)-ethyl]-4-[3-(tetrahydro-pyran-4-yl)-[1,2,4]thiadiazol-5-yl]-piperazine;1-[2-(3,4-Difluoro-phenyl)-ethyl]-4-[3-(tetrahydro-pyran-4-yl)-[1,2,4]thiadiazol-5-yl]-piperazine;3-((3-chlorophenoxy)methyl)-5-(4-(3-methoxyphenethyl)piperazin-1-yl)-1,2,4-thiadiazole;3-(2-(benzyloxy)ethyl)-5-(4-(3-methoxyphenethyl)piperazin-1-yl)-1,2,4-thiadiazole;3-((4-fluorophenoxy)methyl)-5-(4-(3-methoxyphenethyl)piperazin-1-yl)-1,2,4-thiadiazole;3-((4-fluorophenoxy)methyl)-5-(4-(4-methoxyphenethyl)piperazin-1-yl)-1,2,4-thiadiazole;5-(4-(4-methoxyphenethyl)piperazin-1-yl)-3-(trifluoromethyl)-1,2,4-thiadiazole;1-(2-Methyl-benzyl)-4-[3-(tetrahydro-pyran-4-yl)-[1,2,4]thiadiazol-5-yl]-piperazine;and3-(4-chlorophenethyl)-5-(4-(2-methylbenzyl)piperazin-1-yl)-1,2,4-thiadiazole.10. The method according to claim 1, wherein the compound of formula IAis administered in a pharmaceutical preparation containing one or moreof said compound of formula IA and pharmaceutically acceptableexcipients.
 11. A method for reducing TAU-induced cytotoxicity, whichmethod comprises contacting a cell with an effective amount of acompound of formula IA or a pharmaceutically active salt thereof, astereoisomeric form, including an individual diastereoisomer orenantiomer of the compound of formula IA as well as a racemic ornon-racemic mixture thereof;

wherein G¹ is lower alkyl; lower alkyl substituted by one or morehalogens; cycloalkyl; tetrahydropyran-4-yl; phenethyl; phenethylsubstituted by one or more halogens; phenoxymethyl; phenoxymethylsubstituted by one or more halogens; benzyloxy-ethyl; benzyloxy-ethylsubstituted by one or more halogens; or is —NR²R³; R² is hydrogen orlower alkyl; R³ is lower alkyl, tetrahydropyran-4-yl, —CH₂-cycloalkyl orcycloalkyl optionally substituted by lower alkyl substituted by one ormore halogens; or R² and R³ form together with the N-atom to which theyare attached a heterocycloalkyl group with 4 or 5 carbon atoms, which isoptionally substituted by one or more substituents selected from halogenor lower alkyl substituted by one or more halogens; X is —CH₂— or—(CH₂)₂—; Ar is phenyl or pyridinyl; R⁴ is halogen; lower alkyl; loweralkyl substituted by one or more halogens; or lower alkoxy; n is 1 or 2;with the proviso that said compound is not:5-(4-(3-fluorobenzyl)piperazin-1-yl)-3-methyl-1,2,4-thiadiazole, or3-isopropyl-5-(4-(3-(trifluoromethyl)benzyl)piperazin-1-yl)-1,2,4-thiadiazole;wherein the cell is a human neuron.
 12. The method according to claim11, wherein X is —(CH₂)₂—.
 13. The method according to claim 11, whereinG¹ is lower alkyl; cycloalkyl; tetrahydropyran-4-yl; phenoxymethylsubstituted by one or more halogens; benzyloxy-ethyl; or benzyloxy-ethylsubstituted by one or more halogens.
 14. The method according to claim11, wherein G¹ is —NR²R³.
 15. The method according to claim 14, whereinR² is hydrogen and R³ is lower alkyl, tetrahydropyran-4-yl,—CH₂-cycloalkyl, or cycloalkyl optionally substituted by lower alkylsubstituted by one or more halogens.
 16. The method according to claim14, wherein R² and R³ form together with the N-atom to which they areattached a heterocycloalkyl group with 4 or 5 carbon atoms, which isoptionally substituted by one or more substituents selected from halogenor lower alkyl substituted by one or more halogens.
 17. The methodaccording to claim 11, wherein G¹ is selected from: lower alkyl;cycloalkyl; tetrahydropyran-4-yl; phenoxymethyl substituted by one ormore halogens; benzyloxy-ethyl; benzyloxy-ethyl substituted by one ormore halogens; or —NR²R³; and X is —(CH₂)₂.
 18. The method according toclaim 11, wherein G¹ is lower alkyl or phenoxymethyl substituted by oneor more halogens.
 19. The method according to claim 11, wherein saidcompound is selected from the group consisting of:1-[3-(4,4-Difluoro-piperidin-1-yl)-[1,2,4]thiadiazol-5-yl]-4-[2-(4-methoxy-phenyl)-ethyl]-piperazine;1-[2-(4-Chloro-phenyl)-ethyl]-4-[3-(4,4-difluoro-piperidin-1-yl)-[1,2,4]thiadiazol-5-yl]-piperazine;1-[2-(4-Chloro-phenyl)-ethyl]-4-[3-(3,3-difluoro-pyrrolidin-1-yl)-[1,2,4]thiadiazol-5-yl]-piperazine;1-[2-(4-Chloro-phenyl)-ethyl]-4-[3-(4-fluoro-piperidin-1-yl)-[1,2,4]thiadiazol-5-yl]-piperazine;1-[2-(4-Chloro-phenyl)-ethyl]-4-[3-(4-trifluoromethyl-piperidin-1-yl)-[1,2,4]thiadiazol-5-yl]-piperazine;1-[2-(4-Chloro-phenyl)-ethyl]-4-(3-piperidin-1-yl-[1,2,4]thiadiazol-5-yl)-piperazine;(5-{4-[2-(4-Chloro-phenyl)-ethyl]-piperazin-1-yl}-[1,2,4]thiadiazol-3-yl)-cyclopropylmethyl-amine;(5-{4-[2-(4-Chloro-phenyl)-ethyl]-piperazin-1-yl}-[1,2,4]thiadiazol-3-yl)-(tetrahydro-pyran-4-yl)-amine;(5-{4-[2-(4-Chloro-phenyl)-ethyl]-piperazin-1-yl}-[1,2,4]thiadiazol-3-yl)-cyclohexyl-amine;1-[2-(3,4-Difluoro-phenyl)-ethyl]-4-[3-(4,4-difluoro-piperidin-1-yl)-[1,2,4]thiadiazol-5-yl]-piperazine;1-[2-(3,4-Difluoro-phenyl)-ethyl]-4-[3-(3,3-difluoro-pyrrolidin-1-yl)-[1,2,4]thiadiazol-5-yl]-piperazine;1-[2-(3,4-Difluoro-phenyl)-ethyl]-4-[3-(4-fluoro-piperidin-1-yl)-[1,2,4]thiadiazol-5-yl]-piperazine;1-[2-(3,4-Difluoro-phenyl)-ethyl]-4-[3-(4-trifluoromethyl-piperidin-1-yl)-[1,2,4]thiadiazol-5-yl]-piperazine;1-[2-(3,4-Difluoro-phenyl)-ethyl]-4-(3-pyrrolidin-1-yl-[1,2,4]thiadiazol-5-yl)-piperazine;Cyclopropylmethyl-(5-{4-[2-(3,4-difluoro-phenyl)-ethyl]-piperazin-1-yl}-[1,2,4]thiadiazol-3-yl)-amine;(5-{4-[2-(3,4-Difluoro-phenyl)-ethyl]-piperazin-1-yl}-[1,2,4]thiadiazol-3-yl)-(tetrahydro-pyran-4-yl)-amine;Cyclohexyl-(5-{4-[2-(3,4-difluoro-phenyl)-ethyl]-piperazin-1-yl}-[1,2,4]thiadiazol-3-yl)-amine;1-[2-(3,4-Difluoro-phenyl)-ethyl]-4-(3-piperidin-1-yl-[1,2,4]thiadiazol-5-yl)-piperazine;(5-{4-[2-(3,4-Difluoro-phenyl)-ethyl]-piperazin-1-yl}-[1,2,4]thiadiazol-3-yl)-(4-trifluoromethyl-cyclohexyl)-amine;Butyl-(5-{4-[2-(3,4-difluoro-phenyl)-ethyl]-piperazin-1-yl}-[1,2,4]thiadiazol-3-yl)-ethyl-amine;1-(3-Cyclohexyl-[1,2,4]thiadiazol-5-yl)-4-[2-(4-methoxy-phenyl)-ethyl]-piperazine;1-(3-Cyclohexyl-[1,2,4]thiadiazol-5-yl)-4-[2-(3-methoxy-phenyl)-ethyl]-piperazine;1-(3-Butyl-[1,2,4]thiadiazol-5-yl)-4-[2-(4-methoxy-phenyl)-ethyl]-piperazine;1-(3-Cyclopropyl-[1,2,4]thiadiazol-5-yl)-4-[2-(4-methoxy-phenyl)-ethyl]-piperazine;1-(3-Butyl-[1,2,4]thiadiazol-5-yl)-4-[2-(3-methoxy-phenyl)-ethyl]-piperazine;1-(3-Cyclopropyl-[1,2,4]thiadiazol-5-yl)-4-[2-(3-methoxy-phenyl)-ethyl]-piperazine;1-[2-(4-Fluoro-phenyl)-ethyl]-4-[3-(tetrahydro-pyran-4-yl)-[1,2,4]thiadiazol-5-yl]-piperazine;1-[2-(4-Methoxy-phenyl)-ethyl]-4-[3-(tetrahydro-pyran-4-yl)-[1,2,4]thiadiazol-5-yl]-piperazine;1-[2-(2-Methoxy-pyridin-4-yl)-ethyl]-4-[3-(tetrahydro-pyran-4-yl)-[1,2,4]thiadiazol-5-yl]-piperazine;1-[2-(3,4-Difluoro-phenyl)-ethyl]-4-[3-(tetrahydro-pyran-4-yl)-[1,2,4]thiadiazol-5-yl]-piperazine;3-((3-chlorophenoxy)methyl)-5-(4-(3-methoxyphenethyl)piperazin-1-yl)-1,2,4-thiadiazole;3-(2-(benzyloxy)ethyl)-5-(4-(3-methoxyphenethyl)piperazin-1-yl)-1,2,4-thiadiazole;3-((4-fluorophenoxy)methyl)-5-(4-(3-methoxyphenethyl)piperazin-1-yl)-1,2,4-thiadiazole;3-((4-fluorophenoxy)methyl)-5-(4-(4-methoxyphenethyl)piperazin-1-yl)-1,2,4-thiadiazole;5-(4-(4-methoxyphenethyl)piperazin-1-yl)-3-(trifluoromethyl)-1,2,4-thiadiazole;1-(2-Methyl-benzyl)-4-[3-(tetrahydro-pyran-4-yl)-[1,2,4]thiadiazol-5-yl]-piperazine;and3-(4-chlorophenethyl)-5-(4-(2-methylbenzyl)piperazin-1-yl)-1,2,4-thiadiazole.20. The method according to claim 11, wherein the compound of formula IAis administered in a pharmaceutical preparation containing one or moreof said compound of formula IA and pharmaceutically acceptableexcipients.
 21. A method for reducing human neuronal cell death and/ordegeneration, which method comprises contacting a human neuron with aneffective amount of a compound of formula IA or a pharmaceuticallyactive salt thereof, a stereoisomeric form, including an individualdiastereoisomer or enantiomer of the compound of formula IA as well as aracemic or non-racemic mixture thereof;

wherein G¹ is lower alkyl; lower alkyl substituted by one or morehalogens; cycloalkyl; tetrahydropyran-4-yl; phenethyl; phenethylsubstituted by one or more halogens; phenoxymethyl; phenoxymethylsubstituted by one or more halogens; benzyloxy-ethyl; benzyloxy-ethylsubstituted by one or more halogens; or is —NR²R³; R² is hydrogen orlower alkyl; R³ is lower alkyl, tetrahydropyran-4-yl, —CH₂-cycloalkyl orcycloalkyl optionally substituted by lower alkyl substituted by one ormore halogens; or R² and R³ form together with the N-atom to which theyare attached a heterocycloalkyl group with 4 or 5 carbon atoms, which isoptionally substituted by one or more substituents selected from halogenor lower alkyl substituted by one or more halogens; X is —CH₂— or—(CH₂)₂—; Ar is phenyl or pyridinyl; R⁴ is halogen; lower alkyl; loweralkyl substituted by one or more halogens; or lower alkoxy; n is 1 or 2;with the proviso that said compound is not:5-(4-(3-fluorobenzyl)piperazin-1-yl)-3-methyl-1,2,4-thiadiazole or3-isopropyl-5-(4-(3-(trifluoromethyl)benzyl)piperazin-1-yl)-1,2,4-thiadiazole.22. The method according to claim 21, wherein X is —(CH₂)₂—.
 23. Themethod according to claim 21, wherein G¹ is lower alkyl; cycloalkyl;tetrahydropyran-4-yl; phenoxymethyl substituted by one or more halogens;benzyloxy-ethyl; or benzyloxy-ethyl substituted by one or more halogens.24. The method according to claim 21, wherein G¹ is —NR²R³.
 25. Themethod according to claim 24, wherein R² is hydrogen and R³ is loweralkyl, tetrahydropyran-4-yl, —CH₂-cycloalkyl, or cycloalkyl optionallysubstituted by lower alkyl substituted by one or more halogens.
 26. Themethod according to claim 24, wherein R² and R³ form together with theN-atom to which they are attached a heterocycloalkyl group with 4 or 5carbon atoms, which is optionally substituted by one or moresubstituents selected from halogen or lower alkyl substituted by one ormore halogens.
 27. The method according to claim 21, wherein G¹ isselected from: lower alkyl; cycloalkyl; tetrahydropyran-4-yl;phenoxymethyl substituted by one or more halogens; benzyloxy-ethyl;benzyloxy-ethyl substituted by one or more halogens; or —NR²R³; and X is—(CH₂)₂.
 28. The method according to claim 21, wherein G¹ is lower alkylor phenoxymethyl substituted by one or more halogens.
 29. The methodaccording to claim 21, wherein said compound is selected from the groupconsisting of:1-[3-(4,4-Difluoro-piperidin-1-yl)-[1,2,4]thiadiazol-5-yl]-4-[2-(4-methoxy-phenyl)-ethyl]-piperazine;1-[2-(4-Chloro-phenyl)-ethyl]-4-[3-(4,4-difluoro-piperidin-1-yl)-[1,2,4]thiadiazol-5-yl]-piperazine;1-[2-(4-Chloro-phenyl)-ethyl]-4-[3-(3,3-difluoro-pyrrolidin-1-yl)-[1,2,4]thiadiazol-5-yl]-piperazine;1-[2-(4-Chloro-phenyl)-ethyl]-4-[3-(4-fluoro-piperidin-1-yl)-[1,2,4]thiadiazol-5-yl]-piperazine;1-[2-(4-Chloro-phenyl)-ethyl]-4-[3-(4-trifluoromethyl-piperidin-1-yl)-[1,2,4]thiadiazol-5-yl]-piperazine;1-[2-(4-Chloro-phenyl)-ethyl]-4-(3-piperidin-1-yl-[1,2,4]thiadiazol-5-yl)-piperazine;(5-{4-[2-(4-Chloro-phenyl)-ethyl]-piperazin-1-yl}-[1,2,4]thiadiazol-3-yl)-cyclopropylmethyl-amine;(5-{4-[2-(4-Chloro-phenyl)-ethyl]-piperazin-1-yl}-[1,2,4]thiadiazol-3-yl)-(tetrahydro-pyran-4-yl)-amine;(5-{4-[2-(4-Chloro-phenyl)-ethyl]-piperazin-1-yl}-[1,2,4]thiadiazol-3-yl)-cyclohexyl-amine;1-[2-(3,4-Difluoro-phenyl)-ethyl]-4-[3-(4,4-difluoro-piperidin-1-yl)-[1,2,4]thiadiazol-5-yl]-piperazine;1-[2-(3,4-Difluoro-phenyl)-ethyl]-4-[3-(3,3-difluoro-pyrrolidin-1-yl)-[1,2,4]thiadiazol-5-yl]-piperazine;1-[2-(3,4-Difluoro-phenyl)-ethyl]-4-[3-(4-fluoro-piperidin-1-yl)-[1,2,4]thiadiazol-5-yl]-piperazine;1-[2-(3,4-Difluoro-phenyl)-ethyl]-4-[3-(4-trifluoromethyl-piperidin-1-yl)-[1,2,4]thiadiazol-5-yl]-piperazine;1-[2-(3,4-Difluoro-phenyl)-ethyl]-4-(3-pyrrolidin-1-yl-[1,2,4]thiadiazol-5-yl)-piperazine;Cyclopropylmethyl-(5-{4-[2-(3,4-difluoro-phenyl)-ethyl]-piperazin-1-yl}-[1,2,4]thiadiazol-3-yl)-amine;(5-{4-[2-(3,4-Difluoro-phenyl)-ethyl]-piperazin-1-yl}-[1,2,4]thiadiazol-3-yl)-(tetrahydro-pyran-4-yl)-amine;Cyclohexyl-(5-{4-[2-(3,4-difluoro-phenyl)-ethyl]-piperazin-1-yl}-[1,2,4]thiadiazol-3-yl)-amine;1-[2-(3,4-Difluoro-phenyl)-ethyl]-4-(3-piperidin-1-yl-[1,2,4]thiadiazol-5-yl)-piperazine;(5-{4-[2-(3,4-Difluoro-phenyl)-ethyl]-piperazin-1-yl}-[1,2,4]thiadiazol-3-yl)-(4-trifluoromethyl-cyclohexyl)-amine;Butyl-(5-{4-[2-(3,4-difluoro-phenyl)-ethyl]-piperazin-1-yl}-[1,2,4]thiadiazol-3-yl)-ethyl-amine;1-(3-Cyclohexyl-[1,2,4]thiadiazol-5-yl)-4-[2-(4-methoxy-phenyl)-ethyl]-piperazine;1-(3-Cyclohexyl-[1,2,4]thiadiazol-5-yl)-4-[2-(3-methoxy-phenyl)-ethyl]-piperazine;1-(3-Butyl-[1,2,4]thiadiazol-5-yl)-4-[2-(4-methoxy-phenyl)-ethyl]-piperazine;1-(3-Cyclopropyl-[1,2,4]thiadiazol-5-yl)-4-[2-(4-methoxy-phenyl)-ethyl]-piperazine;1-(3-Butyl-[1,2,4]thiadiazol-5-yl)-4-[2-(3-methoxy-phenyl)-ethyl]-piperazine;1-(3-Cyclopropyl-[1,2,4]thiadiazol-5-yl)-4-[2-(3-methoxy-phenyl)-ethyl]-piperazine;1-[2-(4-Fluoro-phenyl)-ethyl]-4-[3-(tetrahydro-pyran-4-yl)-[1,2,4]thiadiazol-5-yl]-piperazine;1-[2-(4-Methoxy-phenyl)-ethyl]-4-[3-(tetrahydro-pyran-4-yl)-[1,2,4]thiadiazol-5-yl]-piperazine;1-[2-(2-Methoxy-pyridin-4-yl)-ethyl]-4-[3-(tetrahydro-pyran-4-yl)-[1,2,4]thiadiazol-5-yl]-piperazine;1-[2-(3,4-Difluoro-phenyl)-ethyl]-4-[3-(tetrahydro-pyran-4-yl)-[1,2,4]thiadiazol-5-yl]-piperazine;3-((3-chlorophenoxy)methyl)-5-(4-(3-methoxyphenethyl)piperazin-1-yl)-1,2,4-thiadiazole;3-(2-(benzyloxy)ethyl)-5-(4-(3-methoxyphenethyl)piperazin-1-yl)-1,2,4-thiadiazole;3-((4-fluorophenoxy)methyl)-5-(4-(3-methoxyphenethyl)piperazin-1-yl)-1,2,4-thiadiazole;3-((4-fluorophenoxy)methyl)-5-(4-(4-methoxyphenethyl)piperazin-1-yl)-1,2,4-thiadiazole;5-(4-(4-methoxyphenethyl)piperazin-1-yl)-3-(trifluoromethyl)-1,2,4-thiadiazole;1-(2-Methyl-benzyl)-4-[3-(tetrahydro-pyran-4-yl)-[1,2,4]thiadiazol-5-yl]-piperazine;and3-(4-chlorophenethyl)-5-(4-(2-methylbenzyl)piperazin-1-yl)-1,2,4-thiadiazole.30. The method according to claim 21, wherein the compound of formula IAis administered in a pharmaceutical preparation containing one or moreof said compound of formula IA and pharmaceutically acceptableexcipients.